Effect of a personalized hemodynamic optimization strategy during septic shock: a stepped-wedge, cluster-randomized, open-label, controlled trial

Effect of a personalized hemodynamic optimization strategy during septic shock: a stepped-wedge, cluster-randomized, open-label, controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (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;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effect of a personalized hemodynamic optimization strategy during septic shock: a stepped-wedge, cluster-randomized, open-label, controlled trial Olivier Huet, Xavier Chapalain, Benjamin Rieu, Thomas Godet, Karim Asehnoune, and 19 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7826002/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Treatment of circulatory failure involves fluid and/or catecholamines infusion. Excessive fluid infusion is associated with worse outcomes, while restrictive fluid strategies show no significant benefits. We aimed to evaluate efficacy of a personalized hemodynamic optimization protocol including three pillars: (i) diagnosing acute circulatory failure, (ii) using a validated hemodynamic monitoring, and (iii) evaluating preload dependency state before any fluid resuscitation. Methods Multicenter, stepped-wedge, cluster-randomized trial involving adult patients with septic shock due to an abdominal or a pulmonary infection. Patients received either usual care (control period), or a personalized hemodynamic optimization strategy (intervention period). Hierarchized primary outcomes included delta SOFA (Sepsis-related Organ Failure Assessment) score from inclusion to day 5, ICU length of stay, hospital length of stay, ventilator-free days, renal failure-free days and catecholamine-free days. Results 517 patients were enrolled: 289 in the control group and 228 in the intervention group. Delta SOFA score was 2.4 in the control group and 1.8 in the intervention group (p = 0.41). ICU length of stay was reduced by 2.5 days (95% CI 0 to 5) in the intervention group. In overall population, other primary outcomes showed no differences. For severe patients (i.e., baseline SOFA ≥ 10), ICU and hospital stay length of stay was also reduced by 3.7 days (95% CI -0.4 to 7.8) and 6.9 days (95% CI -0.7 to 14.4), respectively. Conclusion Although no statistically significant difference was observed in delta SOFA score, a personalized hemodynamic optimization strategy reduced ICU length of stay. Trial Registration ClinicalTrials.gov Identifier NCT03461900 Septic shock Hemodynamic Fluid therapy Personalized medicine Figures Figure 1 Figure 2 Figure 3 Take-home message In this stepped-wedge, cluster-randomized, multicenter trial that included 517 patients, a personalized hemodynamic optimization protocol (based on pre-load dependency evaluation) did not improve early organ dysfunction compare to usual care. However, our study revealed a clinically relevant reduction in the average ICU length of stay for patients who received the personalized hemodynamic optimization strategy. Introduction Sepsis is a global health burden, accounting for 48.9 million new cases annually and responsible for 20% of all deaths worldwide [ 1 ]. Septic shock is marked by acute circulatory failure leading to tissue hypoxia and organ dysfunction [ 2 ]. Fluid and catecholamine administration are the main pillars of acute circulatory failure treatment [ 2 , 3 ]. Hemodynamic management for septic shock patients can be divided in four phases with distinct therapeutic goals: salvage, optimization, stabilization, and de-escalation [ 2 ]. The optimization phase focuses on maintaining cellular oxygen delivery by improving cardiac output and maintaining adequate blood pressure [ 2 ]. While some patients may benefit from fluid administration, others may require catecholamine infusion. Thus, patients may experience harmful effects from inadequate fluid infusion. Fluid overload, defined as a positive fluid balance with clinical signs of tissue edema, leads to prolonged organ dysfunction, longer respiratory support, longer ICU stays, and higher mortality [ 4 – 6 ]. All these findings have prompted to the evaluation of restrictive fluid strategies, testing stringent criteria for fluid administration or promoting the use of vasopressors as first-line therapy [ 7 , 8 ]. Despite reducing fluid volumes, these strategies failed to show significant benefit compare to liberal strategies [ 7 , 8 ]. Guyton’s physiological model explains the varying effects of fluid resuscitation based on preload dependency, linking cardiac output to venous return (i.e., preload) [ 9 ]. At the bedside, preload dependency is defined as an increase of more than 10% in the left ventricle stroke volume following a fluid challenge [ 10 ]. Cardiac output is highly likely to increase after fluid infusion in preload dependent patients [ 10 ]. Conversely, for non-preload dependent patients, the left ventricle cannot enhance its contractility, which may lead to venous congestion and tissue oedema especially for encapsulated organs (liver, kidney and lung) [ 11 ]. Thus, the same volume of infused fluid can either increase cardiac output or cause congestion, depending on the patient’s preload status [ 11 ]. Despite this pathophysiological rational, systematic use of preload dependency evaluation maneuvers to personalize fluid resuscitation remains poorly evaluated [ 12 – 14 ]. The primary aim of this trial was to evaluate the efficacy of a personalized hemodynamic optimization strategy for critically ill patients admitted for a septic shock due to an abdominal or a pulmonary infection. We hypothesized that this strategy would reduce early organ dysfunction, shorten ICU and hospital length of stays, and decrease reliance on organ support compared to usual care. Methods Study design and participants GOAL (Guided fluid Optimization with mini-fluid chALlenge during septic Shock) was a stepped-wedge, cluster-randomized, open-label study conducted in 18 French ICUs. Eligible individuals were all adult patients diagnosed with septic shock according to the international Sepsis-3 criteria [ 15 ]. The main origin of sepsis must be an abdominal (excluding urinary tract infection) or a pulmonary infection. Before inclusion, septic shock must be diagnosed for less than 12 hours, and participants had to be admitted to the ICU for less than three days. Full eligibility criteria are detailed in the Appendix (Supplement, eMethods). The study was approved by the French Ethics Central Committee (number: 18.07.09.57456). Written informed consent was obtained from all patients or their legal surrogates at all sites (Supplement, eMethods). Cluster randomization A computer-generated randomization determined the sequence in which ICUs transitioned from the control to the intervention period. Each ICU (cluster) began the study in the control period (usual care) and transitioned step-by-step to the intervention period (personalized hemodynamic optimization strategy) based on randomization. During the transition period, local investigators paused enrolment and attended a formal 2-hour training session to implement the intervention. Study design is detailed in the Appendix (Supplement, eMethods). Study periods and procedures During the control period, all consecutive eligible patients were included in the study and hemodynamic management was left at the discretion of physicians. Any type of monitoring devices or hemodynamic maneuvers were allowed during this period. Physician were encouraged to follow the latest surviving sepsis campaign guidelines [ 3 ]. Before transitioning from the control to the intervention period, local investigators were unaware of the hemodynamic optimization protocol that would be implemented. During the intervention period, all consecutive eligible patients were included in the study and underwent a hemodynamic optimization strategy according to the following principles: (i) diagnosing patients with an acute circulatory failure according to predefined criteria (eMethods in the Supplement), (ii) using a validated hemodynamic monitoring device, and (iii) evaluating preload dependency state before any fluid resuscitation (Fig. 1 ). If a patient did not have acute circulatory failure, no additional hemodynamic intervention was performed. In cases of acute circulatory failure, clinicians used one of the following devices to measure left ventricular stroke volume and cardiac output: echocardiography (transthoracic or transesophageal), esophageal Doppler, or calibrated transpulmonary thermodilution devices [ 16 ]. A mini-fluid challenge maneuver was performed to test preload dependency by first measuring the variation of left ventricular stroke volume (LVSV) directly via esophageal Doppler or transpulmonary thermodilution, or indirectly with a surrogate such as velocity time index via echocardiography [ 17 , 18 ]. The mini-fluid challenge involved administering a 100 ml intravenous fluid bolus of serum albumin (4% or 5%) over one minute [ 17 , 18 ]. If LVSV increased by 10%, preload dependency was diagnosed [ 17 , 18 ]. Preload dependent patients then received 400 ml of crystalloid solution, and fluid responsiveness was reassessed by measuring cardiac output (with echocardiography) or cardiac index (with esophageal Doppler or transpulmonary thermodilution device). Fluid responsiveness was defined as an increase of 15% in cardiac output or cardiac index. Non-preload dependent patients received no further fluids at that time, and alternative therapies (e.g., catecholamines) were considered. In cases of persistent acute circulatory failure, additional preload dependency tests with mini-fluid challenges were considered, following the same protocol. These principles were applied daily from inclusion until ICU discharge. During the intervention period, any fluid resuscitation without a mini-fluid challenge test was deemed a major protocol deviation. Major and minor protocol deviations are defined in the Appendix (Supplement, eMethods). Outcomes Six primary outcomes were analyzed hierarchically according to the following predefined order: delta SOFA (Sepsis-related Organ Failure Assessment) score from inclusion to day 5, ICU length of stay, hospital length of stay, ventilator-free days at day 28, renal failure-free days at day 28, and catecholamine-free days at day 10. The Delta SOFA score from inclusion to day 5 was defined as the numerical change in SOFA score between inclusion and day 5 (Supplement, eMethods) [ 19 ]. Other primary outcomes definitions are detailed in the Appendix (Supplement, eMethods). Secondary outcomes included all-cause mortality (by day 28 and day 180), time to return home, the Short-Form 36 (SF-36) questionnaire at day 180, and the Post-Traumatic Stress Disorder Checklist (PCL-5) at day 180. Statistical analysis Sample size calculation adhered to the CONSORT extension guidelines for stepped-wedge, cluster-randomized trials [ 20 ]. The study was originally planned in 18 ICUs (clusters) over 38 months, divided into 19 periods of 2 months. To account for potential correlation among patients within the same cluster, we assumed an intra-cluster correlation coefficient (ICC) of 0.1. A sample of 684 patients was needed to achieve 90% power to detect a 2-point difference in delta SOFA score from inclusion to day 5 (first primary outcome) between groups. Hypothesis about the effect sizes were also formulated for the 6 primary outcomes according to a preliminary study (Supplement, eMethods) [ 6 ]. Primary and secondary outcome analyses followed an intention-to-treat approach. Primary outcomes were tested using a prespecified hierarchical procedure, starting with delta SOFA score (first primary outcome). A linear mixed model was used for primary outcome analysis, including a random cluster effect, a fixed time period effect, and the intervention effect. Each primary outcome was tested at a 5% two-sided significance level, contingent on the previous test being statistically significant. If significance failed, subsequent outcomes were reported with least-squares mean differences and 95% Confidence Intervals (CI) calculated by bootstrapping for non-gaussian variables. For the delta SOFA score (first primary outcome), missing data were imputed according to prespecified rules (Supplement, eMethods). Primary outcomes were also compared in three prespecified subgroups, stratified by age (≥ 65 vs < 65), infection source (abdominal vs pulmonary), and baseline SOFA score (≥ 10 vs < 10). Secondary analyses used linear mixed models for continuous variables and generalized estimating equations for categorical ones. These models included a random cluster effect, a fixed time period effect, and the intervention effect. Continuous outcomes were expressed with least-squares mean differences and 95% CIs, while categorical outcomes used Odds Ratios (OR) with 95% CIs. To evaluate the impact of mortality on ICU length of stay, a post-hoc analysis was conducted to explore separately the ICU lengths of stay for patients who survived and for those who did not survive to day 180. For patients who survived, we also performed a post-hoc exploratory analysis for the primary outcomes. For these analyses, a linear mixed model was also applied using the same parameters as previously described. All analyses were conducted independently (Unité de recherche Clinique, Saint Louis-Lariboisière, Paris) using SAS (version 9.4, SAS Institute). Results Study participants From June 4, 2019, to August 9, 2023, 2230 adult patients admitted in the 18 participating ICUs for sepsis were screened for eligibility (eFigure 1 and eFigure 2 in the Supplement). Due to COVID-19, transitions were paused from June 1, 2021, to April 30, 2022, extending the study duration. During this period, centers continued enrolling patients without switching groups. The French Ethics Central Committee approved extending the study until August 9, 2023. Of the 2230 patients screened, 538 patients met the eligibility criteria and 517 (96.1%) were included in the study: 289 during the control period and 228 during the intervention period (eFigure 1 and eFigure 2 in the Supplement). Baseline characteristics were generally well-balanced between the two groups, with the exception of mechanical ventilation and renal replacement therapy, which were more prevalent in the intervention group (Table 1 , eTable 1–2 in the Supplement). The source of infection also showed slight differences between the groups (Table 1 ). Table 1 Patient’s characteristics at baseline. Characteristics Control Intervention (N = 289) (N = 228) Median age (IQR) – year 69 (60–75) 68 (58–76) Male sex – no. (%) 194 (67.1) 139 (61) Median BMI (IQR) – kg/m 2 a 26 (22.4–30.5) 26 (22.5–29.9) Time from starting vasopressor to the inclusion – hours Mean (SD) 8.7 (10.6) 8.6 (9.6) Median (IQR) 5.8 (3–11) 6.5 (3.8–10) Median SOFA score (IQR) b 10 (7–12) 10 (8–12) Pre-existing comorbidities – no. (%) Heart disease 81 (28) 70 (30.7) Ischemic 45 (15.6) 38 (16.7) Arrhythmia 39 (13.5) 33 (14.5) Valvular 16 (5.5) 17 (7.5) Respiratory 67 (23.2) 58 (25.4) COPD 33 (11.4) 27 (11.8) Sleep obstructive apnea 28 (9.7) 22 (9.7) Asthma 14 (4.8) 18 (7.9) Chronic respiratory insufficiency 7 (2.4) 5 (2.2) Long-term oxygen 2 (0.7) 4 (1.8) Diabetes c 69 (23.9) 55 (24.1) Type 2 – non insulin dependent 43 (14.9) 36 (15.8) Type 2 – Insulin dependent 21 (7.3) 18 (7.9) Type 1 4 (1.4) 1 (0.4) Immunosuppression d 44 (15.2) 24 (10.5) Chronic kidney disease 30 (10.4) 25 (11) Long-term dialysis 6 (2.1) 4 (1.8) Cirrhosis 26 (9) 22 (9.7) Source of infection – no. (%) e Abdominal 179 (62.2) 165 (73.7) Pulmonary 102 (35.4) 58 (25.9) Other 8 (2.8) 1 (0.5) Other clinical parameters Lowest cardiac index at inclusion – l/min/m 2 2.7 (2.1–3.2) 2.3 (1.9–2.9) No. of patients (%) 47 (16.3) 119 (52.2) Lowest cardiac output at inclusion – l/min 3.5 (2.4–3.8) 4.1 (3–5.1) No. of patients (%) 13 (4.5) 56 (24.6) Patients under invasive mechanical ventilation – no. (%) f 206 (71.3) 182 (79.8) Median PaO 2 /FiO 2 (IQR) g 190 (137–263) 198 (129–263) PaO 2 /FiO 2 < 200 mmHg – no. (%) 164 (56.8) 123 (54) Median lowest MAP before inclusion (IQR) – mmHg h 57 (50–64) 57 (49–64) Median lowest SAP before inclusion (IQR) – mmHg h 81 (70–93) 84 (70–93) Median highest dose of norepinephrine (IQR) – 𝜇g/kg/min i 0.5 (0.2–1.1) 0·6 (0.3–1.3) Median intravenous fluid received before inclusion (IQR) – ml j 2,477 (1,410–4,195) 2,368 (1,455–3,392) Median higher lactate level (IQR) – mmol/l k 3 (2.3–5.1) 3.4 (2.3–5.6) Acute kidney injury – no. (%) l 186 (64.4) 152 (66.7) KDIGO 1 62 (21.5) 36 (15.8) KDIGO 2 53 (18.3) 41 (18) KDIGO 3 71 (24.6) 75 (32.9) Patients under renal replacement therapy – no. (%) 14 (4.8) 35 (15.4) All continuous data are presented as medians with interquartile ranges (IQR). BMI denotes Body Mass Index, COPD for Chronic Obstructive Pulmonary Disease, MAP for Mean Arterial Pressure and SAP for Systolic Arterial Pressure. a BMI was missing for one patient in the intervention group b The Sepsis-related Organ Failure Assessment (SOFA) score ranges from 0 to 24, with higher scores indicating greater severity 23 . Details about SOFA score calculation are provided in the Appendix (Supplement, eMethods). c Type of diabetes was missing for one patient in the control group. d Immunosuppression included all patients who had received a chemotherapy or corticosteroids within one month prior to inclusion, as well as those with hematological malignancies or solid cancers prior to inclusion. e The reported source of infection refers to the documented or suspected source at inclusion. Data on the source of infection were missing for four patients in the intervention group. f Types of respiratory support were missing for 23 patients in the control group and 8 patients in the intervention group. g PaO 2 /FiO 2 values were missing for 27 patients in the control group and 8 patients in the intervention group. h Values reflect the lowest MAP and the lowest SAP recorded 12 hours prior to inclusion. MAP values were missing for six patients in the control group and three in the intervention group. SAP values were missing for three patients in the control group and two in the intervention group. i Norepinephrine infusion rates reflect the maximum recorded within 24 hours prior to inclusion. Data on norepinephrine were missing for two patients in each group. j Fluids administered within the 24 hours prior to inclusion included all crystalloid solutions (e.g., saline, Ringer, Ringer lactate), colloid solutions (gelatin, albumin [4%, 5%, 20%], dextran, hydroxyethyl starch), blood products (red blood cells, fresh frozen plasma, platelet concentrate), and maintenance fluids containing medications or used for hydration. Data on intravenous fluids were missing for five patients in the control group. k Lactate values reflect the highest levels reported within 24 hours prior to inclusion. Lactate data were missing for nine patients in the control group and four in the intervention group. l Acute kidney injury was determined according to the Kidney Disease Injury and Global Outcomes (KDIGO) criteria. Hemodynamic management From inclusion to day 10, the number of patients who benefit from a hemodynamic monitoring was constantly higher in the intervention group (Fig. 2 A and eTable 3 in the Supplement). Daily fluid balances recorded from day 1 to day 10 were comparable in both groups (Fig. 2 B). At day 5, median cumulative fluid balance was 2,016 ml (-1,454 to 6,044) in the control group and 1,716 ml (-1,345 to 4,874) in the intervention group (eTable 4 in the Supplement). At day 10, the median cumulative fluid balance was 1,155 ml (-3,105 to 5,616) in the control group and 764 ml (-3,328 to 4,853) in the intervention group (eTable 5 in the Supplement). The amount of norepinephrine infusion was similar in both groups (Fig. 2 C and eTable 6 in the Supplement). Major protocol deviations occurred once in 23 patients (10.1%), twice in five (2.2%), and more than twice in four patients (1.8%) in the intervention group (eTable 7 in the Supplement). We also reported a low number of minor protocol deviations overtime (eTable 8 in the Supplement). Primary endpoints Mean delta SOFA score was 2.4 (± 7.1) in the control group and 1.8 (± 7.8) in the intervention group (least-squares mean difference (MD), 0.6; 95% CI, -0.8 to 1.9; p = 0.41) (Table 2 ). In the intervention group, the mean ICU length of stay was reduced by 2.5 days (95% CI 0 to 5) (Table 2 and Fig. 3 A). This reduction was consistent across all prespecified subgroups (Fig. 3 B). It was notably shortened by 3.7 days (95% CI, -0.4 to 7.8) for patients with a baseline SOFA score ≥ 10 (Fig. 3 , panel B). Among survivors, the mean ICU length of stay was reduced by 3.9 days (95% CI, 0.3 to 7.6) (eFigure 3 and eTable 9 in the Supplement). For non-survivors, mean ICU length of stay was comparable between the two groups (MD, 0.4 days; 95% CI, -3 to 3.7) (eFigure 3 in the Supplement). The mean hospital length of stay was 31.2 days (± 34.8) in the control group and 29.6 days (± 33) in the intervention group (MD, 1.7 days; 95% CI, -4.5 to 8.3) (Table 2 ). For patients with a baseline SOFA score ≥ 10, the mean hospital length of stay was reduced by 6.9 days (95% CI, -0.7 to 14.4) (eFigure 5 in the Supplement). At day 28, mean number of ventilator-free days was 17.3 days (± 10.7) in control group and 16.8 days (± 11) in the intervention group (MD, 0.5 days; 95% CI, -1.5 to 2.6) (Table 2 ). Among survivors, the number of ventilator-free days at day 28 was increased by 1.7 days (95% CI -3.3 to -0.1) in the intervention group (eTable 9 in the Supplement). At day 28, mean number of renal failure-free days was 17.1 days (± 11.7) in the control group and 15.7 days (± 11.9) in the intervention group (MD, 1.4 days; 95% CI, -0.8 to 3.6) (Table 2 ). At day 10, mean number of catecholamine-free days was 5.7 days (± 3.8) in the control group and 5.4 days (± 3.8) in the intervention group (MD, 0.3 days; 95% CI, -0.5 to 1) (Table 2 ). Further details on prespecified subgroup analyses and post-hoc analyses are reported in the appendix (eFigure 4–8 and eTable 9 in the Supplement). Table 2 Primary and secondary outcomes. Variable Control Intervention Mean difference Odds Ratio 95% CI P Value (N = 289) (N = 228) Hierarchized primary outcomes Delta SOFA Score a Mean (SD) 2.4 (7.1) 1.8 (7.8) 0.6 – (-0.8 to 1.9) 0.41 Missing b 0 1 ICU length of stay – days Mean (SD) 13.4 (18.1) 10.9 (10.2) 2.5 – (0 to 5) – Missing b 3 1 Hospital length of stay – days Mean (SD) 31.2 (34.8) 29.6 (33) 1·7 – (-4·5 to 8·3) – Missing b 6 6 No. of ventilator-free days at day 28 Mean (SD) 17.3 (10.7) 16.8 (11) 0.5 – (-1.5 to 2.6) – Missing 0 0 No. of renal failure-free days at day 28 Mean (SD) 17.1 (11.7) 15.7 (11.9) 1.4 – (-0.8 to 3.6) – Missing 0 0 No. of catecholamine-free days at day 10 Mean (SD) 5.7 (3.8) 5.4 (3.8) 0.3 – (-0.5 to 1) – Missing 0 0 Secondary outcomes Mortality at day 28 – no./total no. (%) 85/289 (29.4) 82/228 (36) – 1.3 (0.9 to 1.9) – Missing 0 0 Mortality at day 180 – no./total no. (%) 116/289 (40.1) 107/228 (46.3) – 1.2 (0.95 to 1.6) – Missing 0 0 Time from inclusion to return home – days Mean (SD) 74.2 (161.8) 58.2 (56.1) 16 – (-15.6 to 47.6) – Missing b 58 53 Short-Form 36 at day 180 c Physical component Mean (SD) 29.3 (10.1) 30.7 (9.3) -1.4 – (-4.5 to 1.7) – Missing b 77 68 Mental component Mean (SD) 99.1 (4.9) 98.8 (4.3) 0.2 – (-1.2 to 1.6) – Missing b 77 67 PCL-5 questionnaire at day 180 d Mean (SD) 12.9 (11.9) 13.3 (13.5) -0.4 – (-4.4 to 3.7) – Missing b 77 67 Continuous Outcomes are presented as means with standard deviations (SD). Categorical outcomes are presented as numbers (%). For all primary outcomes, confidence intervals (CIs) are calculated by bootstrapping. ICU denotes Intensive Care Unit. a Defined by the numerical variation in Sepsis-related Organ Failure Assessment (SOFA) score between the value calculated at inclusion and the value calculated on day five 23 . Details about delta SOFA score calculation are provided in the Appendix (Supplement, eMethods). b For these outcomes, the number of missing values is reported. For the delta SOFA score (first primary outcome), the missing values reported (six in the control group, nine in the intervention group) were those remaining after the imputation method described in the Appendix (Supplement, eMethods). No other imputation was made for missing data reported in this table. c The Short-Form 36 is a generic questionnaire used to quantify overall quality of life, with two main components: physical and mental component. In each component, a higher score reflects a better quality of life. Details about Short-Form 36 questionnaire are provided in the Appendix (Supplement, eMethods). c The Post-Traumatic Stress Disorder Checklist (PCL-5) is a 20-items questionnaire, corresponding to the DSM-5 diagnosis criteria for post-traumatic stress disorder (PTSD). A higher PCL-5 score reflects a greater proportion of symptoms associated with PTSD. Details about PCL-5 questionnaire are provided in the Appendix (Supplement, eMethods). Secondary endpoints At day 28, mortality occurred in 85 of 289 patients (29.4%) in the control group and 82 of 228 patients (36%) in the intervention group (OR, 1.3; 95% CI, 0.9 to 1.9) (Table 2 ). At day 180, mortality occurred in 116 of 289 patients (40.1%) in the control group and 107 of 228 patients (46.9%) in the intervention group (OR 1.2 [95% CI 0.95 to 1.6]) (Table 2 ). Mean time to return at home was 74.2 days (± 161.8) in the control group and 58.2 days (± 56.1) in the intervention group (MD 16 days [95% CI -15.6 to 47.6]) (Table 2 ). At day 180, SF-36 mental and physical scores and PCL-5 values showed no differences between groups (Table 2 ). Discussion Among patients with septic shock secondary to either an abdominal or a pulmonary infection, a personalized hemodynamic optimization strategy did not significantly improve early organ dysfunction as measured by the SOFA score. Despite the imbalance in baseline characteristics regarding mechanical ventilation and renal replacement therapy against patients in the intervention group, this personalized hemodynamic strategy resulted in a reduction in the mean ICU length of stay by 2.5 days for these patients. Point estimates for ICU length of stay were consistent across all prespecified subgroups, with a notable reduction of 3.7 days for patients with severe conditions (i.e., baseline SOFA score ≥ 10). In these patients, hospital length of stay was also reduced by 6.9 days. Several results reinforced the decrease in the mean ICU length of stay, including the fact that this difference was not influenced by mortality rates and the reduction in the length of mechanical ventilation among survivors by 1.7 days in the intervention group. Overall, compliance to the tested intervention was high. In contrast to the recent trials, the design, study hypothesis, and nature of the hemodynamic intervention differed significantly [ 7 , 8 , 21 ]. Specifically, the GOAL study tested a personalized hemodynamic approach against the ‘restrictive’ and ‘liberal’ approaches previously evaluated [ 7 , 8 , 21 ]. The link between the implemented hemodynamic optimization protocol and the decreased average ICU length of stay is supported by multiple factors. First, the stepped-cluster randomized design minimized contamination bias [ 20 ]. It promoted a clear separation between usual care in the control group and the personalized hemodynamic strategy in the intervention group. Secondly, significant differences in the number of patients who benefit from a hemodynamic monitoring device underscore a distinct management approach between the groups. Consequently, during the control period, fluid administration or catecholamine may have been given irrespective of patients' hemodynamic status. According to Guyton’s model, we hypothesize that the treatment of the acute circulatory failure was more appropriate in the intervention group, potentially reducing venous congestion and fluid overload [ 11 ]. The intervention effect was more pronounced in the most severe patients. In these patients, we hypothesize that persistent capillary leak syndrome may have resulted in extended organ congestion, leading to a longer ICU length of stay [ 22 ]. The strength of our study lies in several key aspects. The stepped-wedge, cluster-randomized design is particularly effective in mitigating contamination bias [ 20 ]. Our study represents the largest trial to date investigating a hemodynamic optimization strategy during septic shock [ 12 – 14 ]. Restrictive eligibility criteria based on the source of infection were chosen to ensure a homogeneous study population regarding organ support level, length of stay, and mortality rate. The primary outcomes are more clinically relevant than surrogate endpoints (e.g. fluid balance) reported in previous studies [ 12 – 14 ]. Compared to other test, the mini-fluid challenge used to assess preload dependency is simple, safe, rapid, and effective, with good predictive performance [ 17 , 18 , 23 ]. It can be performed by any care-team member in ICU or operating room within a short period using a small fluid volume [ 23 ]. Moreover, we allowed three types of monitoring devices to assess preload dependency, reflecting a broad range of clinical practices. Finally, the low rate of major protocol deviation reinforces the feasibility of the strategy. Together, these features highlight the scalability and reliability of the hemodynamic optimization strategy tested in this study. Our study has several limitations. The open-label design may introduce biases. The number of patients included was lower than initially planned, and the observed changes in SOFA scores were smaller than anticipated, reducing the study's statistical power. Imbalances in baseline characteristics, such as mechanical ventilation and renal replacement therapy, might explain the lack of effect on SOFA score and early organ support outcomes. Eventually, the exact mechanisms explaining why the intervention reduced the average ICU length of stay remain complex. Our main hypotheses suggest this could be due to either more appropriate evaluations of preload dependency, more precise hemodynamic monitoring, or both. Conclusion During septic shock due to an abdominal or a pulmonary infection, the implementation of a personalized hemodynamic optimization strategy based on a systematic preload evaluation, did not significantly improve early organ dysfunction measured by SOFA score. However, this personalized strategy led to a meaningful reduction in the mean ICU length of stay, without increasing mortality. Declarations Additional information Acknowledgements: None. Author Contributions: OH, XC and EV conceived, designed the study, and obtained funding for the study. All authors oversaw trial conduction and study management; they equally contributed to data acquisition. OH, XC and EV drafted the manuscript. OH, XC, BM and EV directly accessed and verified the data. OH, XC, BM and EV conducted the analysis and interpreted the data. All authors critically revised and approved the final manuscript. Funding: The GOAL study was publicly funded by the French Ministry of Health (PHRC-n, n°17-0016). The funder had no role in the study design, study conduction, data analysis, data interpretation, or writing of the report. Brest university hospital is the sponsor of the study. Data availability: The dataset and data dictionary were accessible upon request. A de-identified participant dataset could be requested from the corresponding author for consideration. Access to the dataset for scientific purposes may then be granted following a review. Conflict of Interest: OH reports honoraria from Edwards Life Science for lectures. AH reports honoraria from Edwards Life Science, LFB and Octapharma. ML reports honoraria from Edwards Life Science, Shionogi and Grifols, and consulting fees from Viatris and AOP. KA reports honoraria from Vygon, LFB and Baxter. EV reports consulting fees from Abbott and Coloplast. Other authors report no conflict of interest related to this publication. Ethical approval: The study was approved by the French Ethics Central Committee (number: 18.07.09.57456). Consent to participate and consent to publish: Written informed consent was obtained from all patients or their legal surrogates until patients were able to consent at all sites. References Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, Colombara DV, Ikuta KS, Kissoon N, Finfer S, Fleischmann-Struzek C, Machado FR, Reinhart KK, Rowan K, Seymour CW, Watson RS, West TE, Marinho F, Hay SI, Lozano R, Lopez AD, Angus DC, Murray CJL, Naghavi M (2020) Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet 395:200–211 Vincent J-L, De Backer D (2013) Circulatory Shock. N Engl J Med 369:1726–1734 Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, Mcintyre L, Ostermann M, Prescott HC, Schorr C, Simpson S, Wiersinga WJ, Alshamsi F, Angus DC, Arabi Y, Azevedo L, Beale R, Beilman G, Belley-Cote E, Burry L, Cecconi M, Centofanti J, Coz Yataco A, De Waele J, Dellinger RP, Doi K, Du B, Estenssoro E, Ferrer R, Gomersall C, Hodgson C, Møller MH, Iwashyna T, Jacob S, Kleinpell R, Klompas M, Koh Y, Kumar A, Kwizera A, Lobo S, Masur H, McGloughlin S, Mehta S, Mehta Y, Mer M, Nunnally M, Oczkowski S, Osborn T, Papathanassoglou E, Perner A, Puskarich M, Roberts J, Schweickert W, Seckel M, Sevransky J, Sprung CL, Welte T, Zimmerman J, Levy M, Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, Mcintyre L, Ostermann M, Prescott HC, Schorr C, Simpson S, Wiersinga WJ, Alshamsi F, Angus DC, Arabi Y, Azevedo L, Beale R, Beilman G, Belley-Cote E, Burry L, Cecconi M, Centofanti J, Coz Yataco A, De Waele J, Dellinger RP, Doi K, Du B, Estenssoro E, Ferrer R, Gomersall C, Hodgson C, Møller MH, Iwashyna T, Jacob S, Kleinpell R, Klompas M, Koh Y, Kumar A, Kwizera A, Lobo S, Masur H, McGloughlin S, Mehta S, Mehta Y, Mer M, Nunnally M, Oczkowski S, Osborn T, Papathanassoglou E, Perner A, Puskarich M, Roberts J, Schweickert W, Seckel M, Sevransky J, Sprung CL, Welte T, Zimmerman J, Levy M (2021-10-02) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med 2021 47:1147 Sakr Y, Rubatto Birri PN, Kotfis K, Nanchal R, Shah B, Kluge S, Schroeder ME, Marshall JC, Vincent J-L, Intensive Care Over Nations I (2017) Higher Fluid Balance Increases the Risk of Death From Sepsis: Results From a Large International Audit. Crit Care Med 45:386–394 Marik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D (2017) Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med : 1–8 Chapalain X, Vermeersch V, Egreteau P-Y, Prat G, Alavi Z, Vicaut E, Huet O (2019) Association between fluid overload and SOFA score kinetics in septic shock patients: a retrospective multicenter study. J Intensive Care 7:42 The National Heart L, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network (2023) Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med 388:499–510 Meyhoff TS, Hjortrup PB, Wetterslev J, Sivapalan P, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain M, Pettilä V, Møller MH, Kjær M-BN, Lange T, Overgaard-Steensen C, Brand BA, Winther-Olesen M, White JO, Quist L, Westergaard B, Jonsson AB, Hjortsø CJS, Meier N, Jensen TS, Engstrøm J, Nebrich L, Andersen-Ranberg NC, Jensen JV, Joseph NA, Poulsen LM, Herløv LS, Sølling CG, Pedersen SK, Knudsen KK, Straarup TS, Vang ML, Bundgaard H, Rasmussen BS, Aagaard SR, Hildebrandt T, Russell L, Bestle MH, Schønemann-Lund M, Brøchner AC, Elvander CF, Hoffmann SKL, Rasmussen ML, Martin YK, Friberg FF, Seter H, Aslam TN, Ådnøy S, Seidel P, Strand K, Johnstad B, Joelsson-Alm E, Christensen J, Ahlstedt C, Pfortmueller CA, Siegemund M, Greco M, Raděj J, Kříž M, Gould DW, Rowan KM, Mouncey PR, Perner A (2022) Restriction of Intravenous Fluid in ICU Patients with Septic Shock. New England Journal of Medicine 386: 2459–2470 Guyton Arthur C (1968) /03/01) Regulation of Cardiac Output. Anesthesiology 29 Messina A, Calabrò L, Pugliese L, Lulja A, Sopuch A, Rosalba D, Morenghi E, Hernandez G, Monnet X, Cecconi M (2022) Fluid challenge in critically ill patients receiving haemodynamic monitoring: a systematic review and comparison of two decades. Crit Care 26:186 Cecconi M, Aya HD, Geisen M, Ebm C, Fletcher N, Grounds RM, Rhodes A, Cecconi M, Aya HD, Geisen M, Ebm C, Fletcher N, Grounds RM, Rhodes A (2013) (2013-05-08) Changes in the mean systemic filling pressure during a fluid challenge in postsurgical intensive care patients. Intensive Care Med 39:739 Richard J-C, Bayle F, Bourdin G, Leray V, Debord S, Delannoy B, Stoian AC, Wallet F, Yonis H, Guerin C (2015) Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Crit Care 19:5 Chen C, Kollef MH (2015) Targeted fluid minimization following initial resuscitation in septic shock: A pilot study. Chest 148:1462–1469 Douglas IS, Alapat PM, Corl KA, Exline MC, Forni LG, Holder AL, Kaufman DA, Khan A, Levy MM, Martin GS, Sahatjian JA, Seeley E, Self WH, Weingarten JA, Williams M, Hansell DM (2020) Fluid Response Evaluation in Sepsis Hypotension and Shock: A Randomized Clinical Trial. Chest 158:1431–1445 Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche J-D, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent J-L, Angus DC (2016) The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315:801–810 Monnet X, Anguel N, Naudin B, Jabot J, Richard C, Teboul J-L (2010) Arterial pressure-based cardiac output in septic patients: different accuracy of pulse contour and uncalibrated pressure waveform devices. Crit Care 14:R109 Muller L, Toumi M, Bousquet P-J, Riu-Poulenc B, Louart G, Candela D, Zoric L, Suehs C, de La Coussaye J-E, Molinari N, Lefrant J-Y, AzuRéa G (2011) An increase in aortic blood flow after an infusion of 100 ml colloid over 1 minute can predict fluid responsiveness: the mini-fluid challenge study. Anesthesiology 115:541–547 Mallat J, Meddour M, Durville E, Lemyze M, Pepy F, Temime J, Vangrunderbeeck N, Tronchon L, Thevenin D, Tavernier B (2015) Decrease in pulse pressure and stroke volume variations after mini-fluid challenge accurately predicts fluid responsiveness. British Journal of Anaesthesia: aev222 Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, Reinhart CK, Suter PM, Thijs LG (1996) The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 22:707–710 Hemming K, Haines TP, Chilton PJ, Girling AJ, Lilford RJ (2015) -02-06) The stepped wedge cluster randomised trial: rationale, design, analysis, and reporting. BMJ 350:h391 Sivapalan P, Ellekjaer KL, Jessen MK, Meyhoff TS, Cronhjort M, Hjortrup PB, Wetterslev J, Granholm A, Møller MH, Perner A (2023) Lower vs Higher Fluid Volumes in Adult Patients With Sepsis: An Updated Systematic Review With Meta-Analysis and Trial Sequential Analysis. Chest 164:892–912 McMullan RR, McAuley DF, O’Kane CM, Silversides JA (2024) Vascular leak in sepsis: physiological basis and potential therapeutic advances. Crit Care 28:97 Messina A, Dell’Anna A, Baggiani M, Torrini F, Maresca GM, Bennett V, Saderi L, Sotgiu G, Antonelli M, Cecconi M (2019) Functional hemodynamic tests: a systematic review and a metanalysis on the reliability of the end-expiratory occlusion test and of the mini-fluid challenge in predicting fluid responsiveness. Crit Care 23:264 Supplementary Files CONSORTChecklist.pdf GOALstudySupplementalAppendixFinalVersion.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7826002","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":528319047,"identity":"225aa2ea-3c38-4f5a-9127-66806526b323","order_by":0,"name":"Olivier Huet","email":"","orcid":"","institution":"Centre Hospitalier Universitaire de Brest: CHRU de Brest","correspondingAuthor":false,"prefix":"","firstName":"Olivier","middleName":"","lastName":"Huet","suffix":""},{"id":528319048,"identity":"06a47be8-dce0-4c20-8d72-fbd5f7a5b139","order_by":1,"name":"Xavier Chapalain","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-3701-4161","institution":"Centre Hospitalier Universitaire de Brest: CHRU de Brest","correspondingAuthor":true,"prefix":"","firstName":"Xavier","middleName":"","lastName":"Chapalain","suffix":""},{"id":528319049,"identity":"585da620-040d-4f72-91d0-0c6f6c04c665","order_by":2,"name":"Benjamin Rieu","email":"","orcid":"","institution":"CHU Clermont-Ferrand: Centre Hospitalier Universitaire de Clermont-Ferrand","correspondingAuthor":false,"prefix":"","firstName":"Benjamin","middleName":"","lastName":"Rieu","suffix":""},{"id":528319050,"identity":"efd80b9b-3290-4528-8efe-27910aad0916","order_by":3,"name":"Thomas Godet","email":"","orcid":"","institution":"CHU Clermont-Ferrand: Centre Hospitalier Universitaire de Clermont-Ferrand","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Godet","suffix":""},{"id":528319051,"identity":"25606bab-fe2f-4d89-86d3-d9ee9cf4e90b","order_by":4,"name":"Karim Asehnoune","email":"","orcid":"","institution":"CHU Nantes: Centre Hospitalier Universitaire de Nantes","correspondingAuthor":false,"prefix":"","firstName":"Karim","middleName":"","lastName":"Asehnoune","suffix":""},{"id":528319052,"identity":"de0c0271-ece0-49c5-961b-a558bd2bd0f1","order_by":5,"name":"Hervé Floch","email":"","orcid":"","institution":"CHU Brest: CHRU de Brest","correspondingAuthor":false,"prefix":"","firstName":"Hervé","middleName":"","lastName":"Floch","suffix":""},{"id":528319053,"identity":"b1ed747c-edd6-44a9-8214-48aa8261f1ea","order_by":6,"name":"Gwenael Prat","email":"","orcid":"","institution":"Centre Hospitalier Universitaire de Brest: CHRU de Brest","correspondingAuthor":false,"prefix":"","firstName":"Gwenael","middleName":"","lastName":"Prat","suffix":""},{"id":528319054,"identity":"1e8e1a7b-ec6d-4406-a35c-7b840dc876e6","order_by":7,"name":"Jean-Yves Lefrant","email":"","orcid":"","institution":"CHU Nimes: Centre Hospitalier Universitaire de Nimes","correspondingAuthor":false,"prefix":"","firstName":"Jean-Yves","middleName":"","lastName":"Lefrant","suffix":""},{"id":528319055,"identity":"60e11ef5-caa8-4de4-a54f-4ecb349b5fe9","order_by":8,"name":"Mickael Landais","email":"","orcid":"","institution":"CH Le Mans: Centre Hospitalier du Mans","correspondingAuthor":false,"prefix":"","firstName":"Mickael","middleName":"","lastName":"Landais","suffix":""},{"id":528319056,"identity":"b72c59a8-51de-4645-8b47-85c62de61c49","order_by":9,"name":"Martine Ferrandière","email":"","orcid":"","institution":"CHU Tours: Centre Hospitalier Regional Universitaire de Tours","correspondingAuthor":false,"prefix":"","firstName":"Martine","middleName":"","lastName":"Ferrandière","suffix":""},{"id":528319057,"identity":"5e2c3eff-6b34-4d7c-98ea-7b4e0f635119","order_by":10,"name":"Laurent Ducros","email":"","orcid":"","institution":"CHI Toulon - La Seyne sur Mer: Centre Hospitalier Intercommunal Toulon - La Seyne-sur-Mer","correspondingAuthor":false,"prefix":"","firstName":"Laurent","middleName":"","lastName":"Ducros","suffix":""},{"id":528319058,"identity":"7a160a41-76a2-45bf-90de-5346750e0418","order_by":11,"name":"Pierre-Yves Egreteau","email":"","orcid":"","institution":"CH Pays de Morlaix: Centre Hospitalier des Pays de Morlaix","correspondingAuthor":false,"prefix":"","firstName":"Pierre-Yves","middleName":"","lastName":"Egreteau","suffix":""},{"id":528319059,"identity":"55e79c17-58ba-41d8-9f0a-710ce511cf5e","order_by":12,"name":"Sigismond Lasocki","email":"","orcid":"","institution":"CHU Angers: Centre Hospitalier Universitaire d'Angers","correspondingAuthor":false,"prefix":"","firstName":"Sigismond","middleName":"","lastName":"Lasocki","suffix":""},{"id":528319060,"identity":"1a39a279-7b1e-4f79-96d1-788682c33c6a","order_by":13,"name":"Anh Dao Phan","email":"","orcid":"","institution":"HEGP: Hopital Europeen Georges Pompidou","correspondingAuthor":false,"prefix":"","firstName":"Anh","middleName":"Dao","lastName":"Phan","suffix":""},{"id":528319061,"identity":"e2a3274a-7454-442d-bad3-9c88a668b7f3","order_by":14,"name":"Anatole Harrois","email":"","orcid":"","institution":"CHU Bicêtre: Hopital Bicetre","correspondingAuthor":false,"prefix":"","firstName":"Anatole","middleName":"","lastName":"Harrois","suffix":""},{"id":528319062,"identity":"fe7114a5-82a7-494f-9f32-0db8d3798e33","order_by":15,"name":"Alexandre Conia","email":"","orcid":"","institution":"CH Chartres: Hopitaux de Chartres","correspondingAuthor":false,"prefix":"","firstName":"Alexandre","middleName":"","lastName":"Conia","suffix":""},{"id":528319063,"identity":"4b0bce00-456b-46d9-b087-40e0b76ed542","order_by":16,"name":"Pierre-Gildas Guitard","email":"","orcid":"","institution":"CHU Rouen: Centre Hospitalier Universitaire de Rouen","correspondingAuthor":false,"prefix":"","firstName":"Pierre-Gildas","middleName":"","lastName":"Guitard","suffix":""},{"id":528319064,"identity":"e7b9bc4a-1549-4200-807d-0f74284d6994","order_by":17,"name":"Thibault Vieille","email":"","orcid":"","institution":"CHU Besancon: Centre Hospitalier Universitaire de Besancon","correspondingAuthor":false,"prefix":"","firstName":"Thibault","middleName":"","lastName":"Vieille","suffix":""},{"id":528319065,"identity":"71d7337d-c1de-4e1a-9386-7f354d5e68e1","order_by":18,"name":"Mathieu Jamme","email":"","orcid":"","institution":"Hôpital Privé de l’Ouest Parisien: Hopital Prive de l'Ouest Parisien","correspondingAuthor":false,"prefix":"","firstName":"Mathieu","middleName":"","lastName":"Jamme","suffix":""},{"id":528319066,"identity":"86ffb1d6-061d-45d2-a04c-c08b631666e2","order_by":19,"name":"Guentin Saint-Genis","email":"","orcid":"","institution":"CHU Poitiers: Centre Hospitalier Universitaire de Poitiers","correspondingAuthor":false,"prefix":"","firstName":"Guentin","middleName":"","lastName":"Saint-Genis","suffix":""},{"id":528319067,"identity":"0d3b27ef-62da-452d-9fd0-d66724d8f9ba","order_by":20,"name":"Marc Leone","email":"","orcid":"","institution":"APHM: Assistance Publique Hopitaux de Marseille","correspondingAuthor":false,"prefix":"","firstName":"Marc","middleName":"","lastName":"Leone","suffix":""},{"id":528319068,"identity":"02e47c7d-c3d3-4e41-b70c-b076a424c583","order_by":21,"name":"Marie Geslain","email":"","orcid":"","institution":"Centre Hospitalier Universitaire de Brest: CHRU de Brest","correspondingAuthor":false,"prefix":"","firstName":"Marie","middleName":"","lastName":"Geslain","suffix":""},{"id":528319069,"identity":"f8f57239-63f9-4fa3-b9ae-ddd9850e9a56","order_by":22,"name":"Bassirou Mboup","email":"","orcid":"","institution":"Groupe Hospitalier Saint-Louis Lariboisiere et Fernand-Widal","correspondingAuthor":false,"prefix":"","firstName":"Bassirou","middleName":"","lastName":"Mboup","suffix":""},{"id":528319070,"identity":"02d5bbe2-c5da-41af-a3eb-f2845ea59bfc","order_by":23,"name":"Eric Vicaut","email":"","orcid":"","institution":"Groupe Hospitalier Saint-Louis Lariboisiere et Fernand-Widal","correspondingAuthor":false,"prefix":"","firstName":"Eric","middleName":"","lastName":"Vicaut","suffix":""}],"badges":[],"createdAt":"2025-10-10 10:49:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7826002/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7826002/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":94473384,"identity":"8fcfa3c6-0167-49c9-b9b4-154afd763347","added_by":"auto","created_at":"2025-10-27 15:44:15","extension":"xml","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":23507,"visible":true,"origin":"","legend":"","description":"","filename":"icmeICMED2501859.xml","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/9a00cbb537e5ffcd654d8dfb.xml"},{"id":94473056,"identity":"23dbad37-f376-4982-8f51-be00fc67404a","added_by":"auto","created_at":"2025-10-27 15:42:28","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1067,"visible":true,"origin":"","legend":"","description":"","filename":"ICMED250185929402.go.xml","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/f92710024c28233a4df21689.xml"},{"id":94473436,"identity":"aa5fe2ac-e85f-4abe-bf47-5eca065e511c","added_by":"auto","created_at":"2025-10-27 15:44:18","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":835,"visible":true,"origin":"","legend":"","description":"","filename":"ICMED2501859Import.xml","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/d571f6b622be6edd2e5a5d91.xml"},{"id":94473211,"identity":"130f8ada-91c8-4721-a42d-2d38c9b7afb1","added_by":"auto","created_at":"2025-10-27 15:43:16","extension":"xml","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":158815,"visible":true,"origin":"","legend":"","description":"","filename":"ICMED25018590enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/573cd0b1ef1c556023aaa33d.xml"},{"id":94473231,"identity":"0dcc3515-3d77-4494-b094-f760e2229006","added_by":"auto","created_at":"2025-10-27 15:43:29","extension":"emf","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1264032,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.emf","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/02c89949eefbedf980873587.emf"},{"id":94473442,"identity":"d5fc12e9-a8a5-4406-b8f9-c7cd7a2248de","added_by":"auto","created_at":"2025-10-27 15:44:20","extension":"emf","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1007672,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.emf","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/a423696fd86de3b09b2b5f44.emf"},{"id":94473576,"identity":"2ba26d1c-a936-4c80-a467-29d26a4b55d1","added_by":"auto","created_at":"2025-10-27 15:44:54","extension":"emf","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":863936,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.emf","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/3922537e2940f9b8e6e43616.emf"},{"id":94473058,"identity":"86ed51c7-5bbd-4c8f-9c7f-8492bd4fa95b","added_by":"auto","created_at":"2025-10-27 15:42:28","extension":"emf","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":905784,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.emf","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/846e43254831e34e84a5ecd6.emf"},{"id":94473581,"identity":"a42c8df9-cbbe-4d15-bc3c-dca7468cbb88","added_by":"auto","created_at":"2025-10-27 15:44:54","extension":"emf","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":941432,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage5.emf","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/6f297415341982d9cecbf2e0.emf"},{"id":94473603,"identity":"83acc996-0fd5-4b71-9d3b-f5eb736bc8cc","added_by":"auto","created_at":"2025-10-27 15:45:00","extension":"emf","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":408288,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage6.emf","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/358414557d17d8fe6c26f8b0.emf"},{"id":94473293,"identity":"e4d3e9e1-199c-4e77-9cc7-f993ae3cc8b1","added_by":"auto","created_at":"2025-10-27 15:43:47","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":16588,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/2739d1642d4157c5f940b6e5.png"},{"id":94473519,"identity":"28f74eaa-c8fd-4926-81fa-a7a699d5d1e3","added_by":"auto","created_at":"2025-10-27 15:44:44","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10148,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/cdf4cf7b00cd95a07b38f95f.png"},{"id":94473604,"identity":"e23f9508-420d-4edb-9fa8-e96bef0bd337","added_by":"auto","created_at":"2025-10-27 15:45:01","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10054,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/d86980a149b346747c0c0c47.png"},{"id":94473133,"identity":"7d037861-e716-4d3e-a9fd-81f4c0ad6afc","added_by":"auto","created_at":"2025-10-27 15:42:46","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10415,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/8318e33f336e0405e45e21f2.png"},{"id":94473501,"identity":"7aeb6208-d9ee-4779-84fa-8fe7e953a72d","added_by":"auto","created_at":"2025-10-27 15:44:38","extension":"png","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10455,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/5fded39024e291184bdccb9d.png"},{"id":94473364,"identity":"d7c1cd61-f61e-43c2-9f0d-0ae2daae7d6c","added_by":"auto","created_at":"2025-10-27 15:44:06","extension":"png","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11253,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/35728f086dcc2dc544f5e188.png"},{"id":94473355,"identity":"233d0d98-ae14-4291-b3e8-b0b32836fd30","added_by":"auto","created_at":"2025-10-27 15:44:01","extension":"xml","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":156596,"visible":true,"origin":"","legend":"","description":"","filename":"ICMED25018590structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/0e651a752e5a4a79d578e73d.xml"},{"id":94473541,"identity":"3453287d-654b-4e2e-a8ae-4208406ad3ed","added_by":"auto","created_at":"2025-10-27 15:44:48","extension":"html","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":170104,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/6a1b85ce96a8782ea85b0ba8.html"},{"id":94473256,"identity":"c531f591-3ae7-4cf8-b5a4-f71b260325b5","added_by":"auto","created_at":"2025-10-27 15:43:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":192829,"visible":true,"origin":"","legend":"\u003cp\u003eHemodynamic optimization strategy used for patients enrolled during intervention period.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFootnote\u003c/u\u003e: \u003csup\u003ea\u003c/sup\u003e Acute circulatory failure was defined by the presence of at least one of the following criteria: hypotension (systolic arterial pressure \u0026lt; 90 mmHg, mean arterial pressure \u0026lt; 65 mmHg, or a 40% decrease compared to baseline), persistent mottling, recent oliguria (urine output \u0026lt; 0.5 ml/kg/h), a cardiac index \u0026lt; 2 l/min/m², a 50% increase in vasopressor dosage within the last 4 hours, or a lactate level \u0026gt; 2 mmol/l.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Hemodynamic parameters were measured using echocardiography, esophageal Doppler, or a calibrated transpulmonary thermodilution device.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/b6fb3f737d6c2d23d0ec33c8.png"},{"id":94473474,"identity":"cc2ae485-4696-44d0-99c5-fafcd6c2a8ec","added_by":"auto","created_at":"2025-10-27 15:44:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":222696,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of patients who benefit from a hemodynamic monitoring, distribution of daily fluid balance, and the dose of norepinephrine infusion received over time\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFootnote:\u003c/em\u003e Daily fluid balance represents the total amount of fluid administered in ICU minus the total amount of fluid output including urine output, fluid removal by renal replacement therapy, drain losses and other fluid output (e.g., estimated insensible losses, bleeding, or digestive losses). The horizontal lines in the center of each boxes indicates the median daily fluid balance in each group. The lower and upper hinges correspond respectively to the first and third quartiles (the 25\u003csup\u003eth\u003c/sup\u003e and 75\u003csup\u003eth\u003c/sup\u003e percentiles). From each box, the upper whisker extends from the hinge to the largest value no further than 1.5 times IQR from the hinge (where IQR is the interquartile range). From each box, lower whisker extends from the hinge to the smallest value no further than 1.5 times IQR of the hinge.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFootnote:\u003c/em\u003e The horizontal lines in the center of each boxes indicates the median daily fluid balance in each group. The lower and upper hinges correspond respectively to the first and third quartiles (the 25\u003csup\u003eth\u003c/sup\u003e and 75\u003csup\u003eth\u003c/sup\u003e percentiles). From each box, the upper whisker extends from the hinge to the largest value no further than 1.5 times IQR from the hinge (where IQR is the interquartile range). From each box, lower whisker extends from the hinge to the smallest value no further than 1. 5 times IQR of the hinge.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/0a01774eb3bf54d23268679b.png"},{"id":94473247,"identity":"3c12d8dc-7260-4c54-a1a0-b329e08f0d20","added_by":"auto","created_at":"2025-10-27 15:43:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":148900,"visible":true,"origin":"","legend":"\u003cp\u003eICU length of stay.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFootnote:\u003c/em\u003e This figure shows the Kaplan-Meier curve representing the percentage of patients hospitalized in the ICU in both groups, censored at day 90. From enrolment to day 90, no patients were lost to follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFootnote: \u003c/em\u003eThis figure shows least-squares mean differences with 95% confidence intervals (CIs) for ICU length of stay (in days) between the control and intervention groups in all patients and in the three prespecified subgroups. ICU length of stay was missing for three patients in the control group and one patient in the intervention group, these patients are not represented on this figure. CIs have not been adjusted for multiplicity and may not be used for hypothesis testing. The size of each block is proportional to the number of patients included in each corresponding subgroup. Source of infection refers to the documented or suspected infection site at inclusion. Data about source of infection were missing for 4 patients and were not abdominal or pulmonary for nine patients, these patients are not represented on this figure. Sepsis-related Organ Failure Assessment (SOFA) score calculated at baseline, ranges from 0 to 24, with higher scores indicating greater severity \u003csup\u003e23\u003c/sup\u003e. SOFA score calculation is detailed in the Supplementary Appendix. ICU denotes Intensive Care Unit.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/93e35f68f06e164279478bd5.png"},{"id":95657340,"identity":"ee01e209-e54e-4ed7-bc15-d2dcf64c5b40","added_by":"auto","created_at":"2025-11-11 16:20:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1799400,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/c564eafe-d3f9-4bce-a82d-17ce4db39973.pdf"},{"id":94472902,"identity":"457a48e7-2201-40b4-a13d-1f7f3f428122","added_by":"auto","created_at":"2025-10-27 15:42:04","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":143591,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORTChecklist.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/154f582fc4322c266f58bfaa.pdf"},{"id":94473214,"identity":"c850103b-bf45-4393-9a4a-8d2f67cef26f","added_by":"auto","created_at":"2025-10-27 15:43:17","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":1077998,"visible":true,"origin":"","legend":"","description":"","filename":"GOALstudySupplementalAppendixFinalVersion.docx","url":"https://assets-eu.researchsquare.com/files/rs-7826002/v1/6c41791dfedd55e23443e7c8.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eEffect of a personalized hemodynamic optimization strategy during septic shock: a stepped-wedge, cluster-randomized, open-label, controlled trial\u003c/p\u003e","fulltext":[{"header":"Take-home message","content":"\u003cp\u003eIn this stepped-wedge, cluster-randomized, multicenter trial that included 517 patients, a personalized hemodynamic optimization protocol (based on pre-load dependency evaluation) did not improve early organ dysfunction compare to usual care. However, our study revealed a clinically relevant reduction in the average ICU length of stay for patients who received the personalized hemodynamic optimization strategy.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eSepsis is a global health burden, accounting for 48.9\u0026nbsp;million new cases annually and responsible for 20% of all deaths worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Septic shock is marked by acute circulatory failure leading to tissue hypoxia and organ dysfunction [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Fluid and catecholamine administration are the main pillars of acute circulatory failure treatment [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Hemodynamic management for septic shock patients can be divided in four phases with distinct therapeutic goals: salvage, optimization, stabilization, and de-escalation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The optimization phase focuses on maintaining cellular oxygen delivery by improving cardiac output and maintaining adequate blood pressure [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. While some patients may benefit from fluid administration, others may require catecholamine infusion. Thus, patients may experience harmful effects from inadequate fluid infusion. Fluid overload, defined as a positive fluid balance with clinical signs of tissue edema, leads to prolonged organ dysfunction, longer respiratory support, longer ICU stays, and higher mortality [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. All these findings have prompted to the evaluation of restrictive fluid strategies, testing stringent criteria for fluid administration or promoting the use of vasopressors as first-line therapy [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Despite reducing fluid volumes, these strategies failed to show significant benefit compare to liberal strategies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eGuyton\u0026rsquo;s physiological model explains the varying effects of fluid resuscitation based on preload dependency, linking cardiac output to venous return (i.e., preload) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. At the bedside, preload dependency is defined as an increase of more than 10% in the left ventricle stroke volume following a fluid challenge [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Cardiac output is highly likely to increase after fluid infusion in preload dependent patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Conversely, for non-preload dependent patients, the left ventricle cannot enhance its contractility, which may lead to venous congestion and tissue oedema especially for encapsulated organs (liver, kidney and lung) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Thus, the same volume of infused fluid can either increase cardiac output or cause congestion, depending on the patient\u0026rsquo;s preload status [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Despite this pathophysiological rational, systematic use of preload dependency evaluation maneuvers to personalize fluid resuscitation remains poorly evaluated [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe primary aim of this trial was to evaluate the efficacy of a personalized hemodynamic optimization strategy for critically ill patients admitted for a septic shock due to an abdominal or a pulmonary infection. We hypothesized that this strategy would reduce early organ dysfunction, shorten ICU and hospital length of stays, and decrease reliance on organ support compared to usual care.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and participants\u003c/h2\u003e\u003cp\u003eGOAL (Guided fluid Optimization with mini-fluid chALlenge during septic Shock) was a stepped-wedge, cluster-randomized, open-label study conducted in 18 French ICUs. Eligible individuals were all adult patients diagnosed with septic shock according to the international Sepsis-3 criteria [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The main origin of sepsis must be an abdominal (excluding urinary tract infection) or a pulmonary infection. Before inclusion, septic shock must be diagnosed for less than 12 hours, and participants had to be admitted to the ICU for less than three days. Full eligibility criteria are detailed in the Appendix (Supplement, eMethods). The study was approved by the French Ethics Central Committee (number: 18.07.09.57456). Written informed consent was obtained from all patients or their legal surrogates at all sites (Supplement, eMethods).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eCluster randomization\u003c/h3\u003e\n\u003cp\u003eA computer-generated randomization determined the sequence in which ICUs transitioned from the control to the intervention period. Each ICU (cluster) began the study in the control period (usual care) and transitioned step-by-step to the intervention period (personalized hemodynamic optimization strategy) based on randomization. During the transition period, local investigators paused enrolment and attended a formal 2-hour training session to implement the intervention. Study design is detailed in the Appendix (Supplement, eMethods).\u003c/p\u003e\n\u003ch3\u003eStudy periods and procedures\u003c/h3\u003e\n\u003cp\u003eDuring the control period, all consecutive eligible patients were included in the study and hemodynamic management was left at the discretion of physicians. Any type of monitoring devices or hemodynamic maneuvers were allowed during this period. Physician were encouraged to follow the latest surviving sepsis campaign guidelines [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Before transitioning from the control to the intervention period, local investigators were unaware of the hemodynamic optimization protocol that would be implemented.\u003c/p\u003e\u003cp\u003eDuring the intervention period, all consecutive eligible patients were included in the study and underwent a hemodynamic optimization strategy according to the following principles: (i) diagnosing patients with an acute circulatory failure according to predefined criteria (eMethods in the Supplement), (ii) using a validated hemodynamic monitoring device, and (iii) evaluating preload dependency state before any fluid resuscitation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). If a patient did not have acute circulatory failure, no additional hemodynamic intervention was performed. In cases of acute circulatory failure, clinicians used one of the following devices to measure left ventricular stroke volume and cardiac output: echocardiography (transthoracic or transesophageal), esophageal Doppler, or calibrated transpulmonary thermodilution devices [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. A mini-fluid challenge maneuver was performed to test preload dependency by first measuring the variation of left ventricular stroke volume (LVSV) directly via esophageal Doppler or transpulmonary thermodilution, or indirectly with a surrogate such as velocity time index via echocardiography [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The mini-fluid challenge involved administering a 100 ml intravenous fluid bolus of serum albumin (4% or 5%) over one minute [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. If LVSV increased by 10%, preload dependency was diagnosed [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Preload dependent patients then received 400 ml of crystalloid solution, and fluid responsiveness was reassessed by measuring cardiac output (with echocardiography) or cardiac index (with esophageal Doppler or transpulmonary thermodilution device). Fluid responsiveness was defined as an increase of 15% in cardiac output or cardiac index. Non-preload dependent patients received no further fluids at that time, and alternative therapies (e.g., catecholamines) were considered. In cases of persistent acute circulatory failure, additional preload dependency tests with mini-fluid challenges were considered, following the same protocol. These principles were applied daily from inclusion until ICU discharge. During the intervention period, any fluid resuscitation without a mini-fluid challenge test was deemed a major protocol deviation. Major and minor protocol deviations are defined in the Appendix (Supplement, eMethods).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eSix primary outcomes were analyzed hierarchically according to the following predefined order: delta SOFA (Sepsis-related Organ Failure Assessment) score from inclusion to day 5, ICU length of stay, hospital length of stay, ventilator-free days at day 28, renal failure-free days at day 28, and catecholamine-free days at day 10. The Delta SOFA score from inclusion to day 5 was defined as the numerical change in SOFA score between inclusion and day 5 (Supplement, eMethods) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Other primary outcomes definitions are detailed in the Appendix (Supplement, eMethods).\u003c/p\u003e\u003cp\u003eSecondary outcomes included all-cause mortality (by day 28 and day 180), time to return home, the Short-Form 36 (SF-36) questionnaire at day 180, and the Post-Traumatic Stress Disorder Checklist (PCL-5) at day 180.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eSample size calculation adhered to the CONSORT extension guidelines for stepped-wedge, cluster-randomized trials [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The study was originally planned in 18 ICUs (clusters) over 38 months, divided into 19 periods of 2 months. To account for potential correlation among patients within the same cluster, we assumed an intra-cluster correlation coefficient (ICC) of 0.1. A sample of 684 patients was needed to achieve 90% power to detect a 2-point difference in delta SOFA score from inclusion to day 5 (first primary outcome) between groups. Hypothesis about the effect sizes were also formulated for the 6 primary outcomes according to a preliminary study (Supplement, eMethods) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePrimary and secondary outcome analyses followed an intention-to-treat approach.\u003c/p\u003e\u003cp\u003ePrimary outcomes were tested using a prespecified hierarchical procedure, starting with delta SOFA score (first primary outcome). A linear mixed model was used for primary outcome analysis, including a random cluster effect, a fixed time period effect, and the intervention effect. Each primary outcome was tested at a 5% two-sided significance level, contingent on the previous test being statistically significant. If significance failed, subsequent outcomes were reported with least-squares mean differences and 95% Confidence Intervals (CI) calculated by bootstrapping for non-gaussian variables. For the delta SOFA score (first primary outcome), missing data were imputed according to prespecified rules (Supplement, eMethods). Primary outcomes were also compared in three prespecified subgroups, stratified by age (\u0026ge;\u0026thinsp;65 \u003cem\u003evs\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;65), infection source (abdominal \u003cem\u003evs\u003c/em\u003e pulmonary), and baseline SOFA score (\u0026ge;\u0026thinsp;10 \u003cem\u003evs\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;10).\u003c/p\u003e\u003cp\u003eSecondary analyses used linear mixed models for continuous variables and generalized estimating equations for categorical ones. These models included a random cluster effect, a fixed time period effect, and the intervention effect. Continuous outcomes were expressed with least-squares mean differences and 95% CIs, while categorical outcomes used Odds Ratios (OR) with 95% CIs.\u003c/p\u003e\u003cp\u003eTo evaluate the impact of mortality on ICU length of stay, a post-hoc analysis was conducted to explore separately the ICU lengths of stay for patients who survived and for those who did not survive to day 180. For patients who survived, we also performed a post-hoc exploratory analysis for the primary outcomes. For these analyses, a linear mixed model was also applied using the same parameters as previously described.\u003c/p\u003e\u003cp\u003eAll analyses were conducted independently (Unit\u0026eacute; de recherche Clinique, Saint Louis-Lariboisi\u0026egrave;re, Paris) using SAS (version 9.4, SAS Institute).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eStudy participants\u003c/h2\u003e\u003cp\u003eFrom June 4, 2019, to August 9, 2023, 2230 adult patients admitted in the 18 participating ICUs for sepsis were screened for eligibility (eFigure 1 and eFigure 2 in the Supplement). Due to COVID-19, transitions were paused from June 1, 2021, to April 30, 2022, extending the study duration. During this period, centers continued enrolling patients without switching groups. The French Ethics Central Committee approved extending the study until August 9, 2023. Of the 2230 patients screened, 538 patients met the eligibility criteria and 517 (96.1%) were included in the study: 289 during the control period and 228 during the intervention period (eFigure 1 and eFigure 2 in the Supplement). Baseline characteristics were generally well-balanced between the two groups, with the exception of mechanical ventilation and renal replacement therapy, which were more prevalent in the intervention group (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, eTable 1\u0026ndash;2 in the Supplement). The source of infection also showed slight differences between the groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient\u0026rsquo;s characteristics at baseline.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eControl\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIntervention\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;289)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;228)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian age (IQR) \u0026ndash; year\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e69 (60\u0026ndash;75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e68 (58\u0026ndash;76)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale sex \u0026ndash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e194 (67.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e139 (61)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian BMI (IQR) \u0026ndash; kg/m\u003csup\u003e2 a\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26 (22.4\u0026ndash;30.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26 (22.5\u0026ndash;29.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTime from starting vasopressor to the inclusion \u0026ndash; hours\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.7 (10.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8.6 (9.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.8 (3\u0026ndash;11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.5 (3.8\u0026ndash;10)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian SOFA score (IQR) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (7\u0026ndash;12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (8\u0026ndash;12)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePre-existing comorbidities \u0026ndash; no. (%)\u003c/p\u003e\u003cp\u003eHeart disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e81 (28)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e70 (30.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIschemic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45 (15.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38 (16.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eArrhythmia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39 (13.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33 (14.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eValvular\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (5.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17 (7.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRespiratory\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e67 (23.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e58 (25.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCOPD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33 (11.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27 (11.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSleep obstructive apnea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (9.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22 (9.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAsthma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (4.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (7.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic respiratory insufficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (2.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (2.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLong-term oxygen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (0.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (1.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e69 (23.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e55 (24.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eType 2 \u0026ndash; non insulin dependent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43 (14.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36 (15.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eType 2 \u0026ndash; Insulin dependent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21 (7.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (7.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eType 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (1.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (0.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eImmunosuppression \u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44 (15.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24 (10.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic kidney disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30 (10.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25 (11)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLong-term dialysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (1.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCirrhosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22 (9.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSource of infection \u0026ndash; no. (%)\u003c/b\u003e \u003csup\u003e\u003cb\u003ee\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbdominal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e179 (62.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e165 (73.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePulmonary\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e102 (35.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e58 (25.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (2.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (0.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOther clinical parameters\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLowest cardiac index at inclusion \u0026ndash; l/min/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.7 (2.1\u0026ndash;3.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.3 (1.9\u0026ndash;2.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo. of patients (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e47 (16.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e119 (52.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLowest cardiac output at inclusion \u0026ndash; l/min\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.5 (2.4\u0026ndash;3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.1 (3\u0026ndash;5.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo. of patients (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (4.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e56 (24.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatients under invasive mechanical ventilation \u0026ndash; no. (%) \u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e206 (71.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e182 (79.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e (IQR) \u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e190 (137\u0026ndash;263)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e198 (129\u0026ndash;263)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;200 mmHg \u0026ndash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e164 (56.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e123 (54)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian lowest MAP before inclusion (IQR) \u0026ndash; mmHg \u003csup\u003eh\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57 (50\u0026ndash;64)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e57 (49\u0026ndash;64)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian lowest SAP before inclusion (IQR) \u0026ndash; mmHg \u003csup\u003eh\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e81 (70\u0026ndash;93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e84 (70\u0026ndash;93)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian highest dose of norepinephrine (IQR) \u0026ndash; \u0026#120583;g/kg/min \u003csup\u003ei\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.5 (0.2\u0026ndash;1.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u0026middot;6 (0.3\u0026ndash;1.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian intravenous fluid received before inclusion (IQR) \u0026ndash; ml \u003csup\u003ej\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,477 (1,410\u0026ndash;4,195)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2,368 (1,455\u0026ndash;3,392)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian higher lactate level (IQR) \u0026ndash; mmol/l \u003csup\u003ek\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (2.3\u0026ndash;5.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.4 (2.3\u0026ndash;5.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAcute kidney injury \u0026ndash; no. (%) \u003csup\u003el\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e186 (64.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e152 (66.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKDIGO 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e62 (21.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36 (15.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKDIGO 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53 (18.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e41 (18)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKDIGO 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e71 (24.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e75 (32.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatients under renal replacement therapy \u0026ndash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (4.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35 (15.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eAll continuous data are presented as medians with interquartile ranges (IQR). BMI denotes Body Mass Index, COPD for Chronic Obstructive Pulmonary Disease, MAP for Mean Arterial Pressure and SAP for Systolic Arterial Pressure.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003ea\u003c/sup\u003e BMI was missing for one patient in the intervention group\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003eb\u003c/sup\u003e The Sepsis-related Organ Failure Assessment (SOFA) score ranges from 0 to 24, with higher scores indicating greater severity \u003csup\u003e23\u003c/sup\u003e. Details about SOFA score calculation are provided in the Appendix (Supplement, eMethods).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003ec\u003c/sup\u003e Type of diabetes was missing for one patient in the control group.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003ed\u003c/sup\u003e Immunosuppression included all patients who had received a chemotherapy or corticosteroids within one month prior to inclusion, as well as those with hematological malignancies or solid cancers prior to inclusion.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003ee\u003c/sup\u003e The reported source of infection refers to the documented or suspected source at inclusion. Data on the source of infection were missing for four patients in the intervention group.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003ef\u003c/sup\u003e Types of respiratory support were missing for 23 patients in the control group and 8 patients in the intervention group.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003eg\u003c/sup\u003e PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e values were missing for 27 patients in the control group and 8 patients in the intervention group.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003eh\u003c/sup\u003e Values reflect the lowest MAP and the lowest SAP recorded 12 hours prior to inclusion. MAP values were missing for six patients in the control group and three in the intervention group. SAP values were missing for three patients in the control group and two in the intervention group.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003ei\u003c/sup\u003e Norepinephrine infusion rates reflect the maximum recorded within 24 hours prior to inclusion. Data on norepinephrine were missing for two patients in each group.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003ej\u003c/sup\u003e Fluids administered within the 24 hours prior to inclusion included all crystalloid solutions (e.g., saline, Ringer, Ringer lactate), colloid solutions (gelatin, albumin [4%, 5%, 20%], dextran, hydroxyethyl starch), blood products (red blood cells, fresh frozen plasma, platelet concentrate), and maintenance fluids containing medications or used for hydration. Data on intravenous fluids were missing for five patients in the control group.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003ek\u003c/sup\u003e Lactate values reflect the highest levels reported within 24 hours prior to inclusion. Lactate data were missing for nine patients in the control group and four in the intervention group.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003el\u003c/sup\u003e Acute kidney injury was determined according to the Kidney Disease Injury and Global Outcomes (KDIGO) criteria.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eHemodynamic management\u003c/h3\u003e\n\u003cp\u003eFrom inclusion to day 10, the number of patients who benefit from a hemodynamic monitoring was constantly higher in the intervention group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and eTable 3 in the Supplement). Daily fluid balances recorded from day 1 to day 10 were comparable in both groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). At day 5, median cumulative fluid balance was 2,016 ml (-1,454 to 6,044) in the control group and 1,716 ml (-1,345 to 4,874) in the intervention group (eTable 4 in the Supplement). At day 10, the median cumulative fluid balance was 1,155 ml (-3,105 to 5,616) in the control group and 764 ml (-3,328 to 4,853) in the intervention group (eTable 5 in the Supplement). The amount of norepinephrine infusion was similar in both groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC and eTable 6 in the Supplement). Major protocol deviations occurred once in 23 patients (10.1%), twice in five (2.2%), and more than twice in four patients (1.8%) in the intervention group (eTable 7 in the Supplement). We also reported a low number of minor protocol deviations overtime (eTable 8 in the Supplement).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003ePrimary endpoints\u003c/h2\u003e\u003cp\u003eMean delta SOFA score was 2.4 (\u0026plusmn;\u0026thinsp;7.1) in the control group and 1.8 (\u0026plusmn;\u0026thinsp;7.8) in the intervention group (least-squares mean difference (MD), 0.6; 95% CI, -0.8 to 1.9; p\u0026thinsp;=\u0026thinsp;0.41) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In the intervention group, the mean ICU length of stay was reduced by 2.5 days (95% CI 0 to 5) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). This reduction was consistent across all prespecified subgroups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). It was notably shortened by 3.7 days (95% CI, -0.4 to 7.8) for patients with a baseline SOFA score\u0026thinsp;\u0026ge;\u0026thinsp;10 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, panel B). Among survivors, the mean ICU length of stay was reduced by 3.9 days (95% CI, 0.3 to 7.6) (eFigure 3 and eTable 9 in the Supplement). For non-survivors, mean ICU length of stay was comparable between the two groups (MD, 0.4 days; 95% CI, -3 to 3.7) (eFigure 3 in the Supplement). The mean hospital length of stay was 31.2 days (\u0026plusmn;\u0026thinsp;34.8) in the control group and 29.6 days (\u0026plusmn;\u0026thinsp;33) in the intervention group (MD, 1.7 days; 95% CI, -4.5 to 8.3) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). For patients with a baseline SOFA score\u0026thinsp;\u0026ge;\u0026thinsp;10, the mean hospital length of stay was reduced by 6.9 days (95% CI, -0.7 to 14.4) (eFigure 5 in the Supplement). At day 28, mean number of ventilator-free days was 17.3 days (\u0026plusmn;\u0026thinsp;10.7) in control group and 16.8 days (\u0026plusmn;\u0026thinsp;11) in the intervention group (MD, 0.5 days; 95% CI, -1.5 to 2.6) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among survivors, the number of ventilator-free days at day 28 was increased by 1.7 days (95% CI -3.3 to -0.1) in the intervention group (eTable 9 in the Supplement). At day 28, mean number of renal failure-free days was 17.1 days (\u0026plusmn;\u0026thinsp;11.7) in the control group and 15.7 days (\u0026plusmn;\u0026thinsp;11.9) in the intervention group (MD, 1.4 days; 95% CI, -0.8 to 3.6) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). At day 10, mean number of catecholamine-free days was 5.7 days (\u0026plusmn;\u0026thinsp;3.8) in the control group and 5.4 days (\u0026plusmn;\u0026thinsp;3.8) in the intervention group (MD, 0.3 days; 95% CI, -0.5 to 1) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Further details on prespecified subgroup analyses and post-hoc analyses are reported in the appendix (eFigure 4\u0026ndash;8 and eTable 9 in the Supplement).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePrimary and secondary outcomes.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eControl\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIntervention\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eMean difference\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eOdds Ratio\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eP Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;289)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;228)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHierarchized primary outcomes\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDelta SOFA Score \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.4 (7.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.8 (7.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(-0.8 to 1.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.41\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eICU length of stay \u0026ndash; days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13.4 (18.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.9 (10.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0 to 5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHospital length of stay \u0026ndash; days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31.2 (34.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29.6 (33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u0026middot;7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(-4\u0026middot;5 to 8\u0026middot;3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo. of ventilator-free days at day 28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17.3 (10.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16.8 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(-1.5 to 2.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo. of renal failure-free days at day 28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17.1 (11.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15.7 (11.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(-0.8 to 3.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo. of catecholamine-free days at day 10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.7 (3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.4 (3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(-0.5 to 1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSecondary outcomes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMortality at day 28 \u0026ndash; no./total no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e85/289 (29.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e82/228 (36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.9 to 1.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMortality at day 180 \u0026ndash; no./total no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e116/289 (40.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e107/228 (46.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.95 to 1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTime from inclusion to return home \u0026ndash; days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e74.2 (161.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e58.2 (56.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(-15.6 to 47.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eShort-Form 36 at day 180 \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePhysical component\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29.3 (10.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30.7 (9.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(-4.5 to 1.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMental component\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.1 (4.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e98.8 (4.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(-1.2 to 1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePCL-5 questionnaire at day 180 \u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12.9 (11.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13.3 (13.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(-4.4 to 3.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eContinuous Outcomes are presented as means with standard deviations (SD). Categorical outcomes are presented as numbers (%). For all primary outcomes, confidence intervals (CIs) are calculated by bootstrapping. ICU denotes Intensive Care Unit.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003ea\u003c/sup\u003e Defined by the numerical variation in Sepsis-related Organ Failure Assessment (SOFA) score between the value calculated at inclusion and the value calculated on day five \u003csup\u003e23\u003c/sup\u003e. Details about delta SOFA score calculation are provided in the Appendix (Supplement, eMethods).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003eb\u003c/sup\u003e For these outcomes, the number of missing values is reported. For the delta SOFA score (first primary outcome), the missing values reported (six in the control group, nine in the intervention group) were those remaining after the imputation method described in the Appendix (Supplement, eMethods). No other imputation was made for missing data reported in this table.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003ec\u003c/sup\u003e The Short-Form 36 is a generic questionnaire used to quantify overall quality of life, with two main components: physical and mental component. In each component, a higher score reflects a better quality of life. Details about Short-Form 36 questionnaire are provided in the Appendix (Supplement, eMethods).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003ec\u003c/sup\u003e The Post-Traumatic Stress Disorder Checklist (PCL-5) is a 20-items questionnaire, corresponding to the DSM-5 diagnosis criteria for post-traumatic stress disorder (PTSD). A higher PCL-5 score reflects a greater proportion of symptoms associated with PTSD. Details about PCL-5 questionnaire are provided in the Appendix (Supplement, eMethods).\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eSecondary endpoints\u003c/h2\u003e\u003cp\u003eAt day 28, mortality occurred in 85 of 289 patients (29.4%) in the control group and 82 of 228 patients (36%) in the intervention group (OR, 1.3; 95% CI, 0.9 to 1.9) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). At day 180, mortality occurred in 116 of 289 patients (40.1%) in the control group and 107 of 228 patients (46.9%) in the intervention group (OR 1.2 [95% CI 0.95 to 1.6]) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Mean time to return at home was 74.2 days (\u0026plusmn;\u0026thinsp;161.8) in the control group and 58.2 days (\u0026plusmn;\u0026thinsp;56.1) in the intervention group (MD 16 days [95% CI -15.6 to 47.6]) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). At day 180, SF-36 mental and physical scores and PCL-5 values showed no differences between groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAmong patients with septic shock secondary to either an abdominal or a pulmonary infection, a personalized hemodynamic optimization strategy did not significantly improve early organ dysfunction as measured by the SOFA score. Despite the imbalance in baseline characteristics regarding mechanical ventilation and renal replacement therapy against patients in the intervention group, this personalized hemodynamic strategy resulted in a reduction in the mean ICU length of stay by 2.5 days for these patients. Point estimates for ICU length of stay were consistent across all prespecified subgroups, with a notable reduction of 3.7 days for patients with severe conditions (i.e., baseline SOFA score\u0026thinsp;\u0026ge;\u0026thinsp;10). In these patients, hospital length of stay was also reduced by 6.9 days. Several results reinforced the decrease in the mean ICU length of stay, including the fact that this difference was not influenced by mortality rates and the reduction in the length of mechanical ventilation among survivors by 1.7 days in the intervention group. Overall, compliance to the tested intervention was high.\u003c/p\u003e\u003cp\u003eIn contrast to the recent trials, the design, study hypothesis, and nature of the hemodynamic intervention differed significantly [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Specifically, the GOAL study tested a personalized hemodynamic approach against the \u0026lsquo;restrictive\u0026rsquo; and \u0026lsquo;liberal\u0026rsquo; approaches previously evaluated [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The link between the implemented hemodynamic optimization protocol and the decreased average ICU length of stay is supported by multiple factors. First, the stepped-cluster randomized design minimized contamination bias [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. It promoted a clear separation between usual care in the control group and the personalized hemodynamic strategy in the intervention group. Secondly, significant differences in the number of patients who benefit from a hemodynamic monitoring device underscore a distinct management approach between the groups. Consequently, during the control period, fluid administration or catecholamine may have been given irrespective of patients' hemodynamic status.\u003c/p\u003e\u003cp\u003eAccording to Guyton\u0026rsquo;s model, we hypothesize that the treatment of the acute circulatory failure was more appropriate in the intervention group, potentially reducing venous congestion and fluid overload [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The intervention effect was more pronounced in the most severe patients. In these patients, we hypothesize that persistent capillary leak syndrome may have resulted in extended organ congestion, leading to a longer ICU length of stay [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe strength of our study lies in several key aspects. The stepped-wedge, cluster-randomized design is particularly effective in mitigating contamination bias [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Our study represents the largest trial to date investigating a hemodynamic optimization strategy during septic shock [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Restrictive eligibility criteria based on the source of infection were chosen to ensure a homogeneous study population regarding organ support level, length of stay, and mortality rate. The primary outcomes are more clinically relevant than surrogate endpoints (e.g. fluid balance) reported in previous studies [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Compared to other test, the mini-fluid challenge used to assess preload dependency is simple, safe, rapid, and effective, with good predictive performance [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. It can be performed by any care-team member in ICU or operating room within a short period using a small fluid volume [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Moreover, we allowed three types of monitoring devices to assess preload dependency, reflecting a broad range of clinical practices. Finally, the low rate of major protocol deviation reinforces the feasibility of the strategy. Together, these features highlight the scalability and reliability of the hemodynamic optimization strategy tested in this study.\u003c/p\u003e\u003cp\u003eOur study has several limitations. The open-label design may introduce biases. The number of patients included was lower than initially planned, and the observed changes in SOFA scores were smaller than anticipated, reducing the study's statistical power. Imbalances in baseline characteristics, such as mechanical ventilation and renal replacement therapy, might explain the lack of effect on SOFA score and early organ support outcomes. Eventually, the exact mechanisms explaining why the intervention reduced the average ICU length of stay remain complex. Our main hypotheses suggest this could be due to either more appropriate evaluations of preload dependency, more precise hemodynamic monitoring, or both.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eDuring septic shock due to an abdominal or a pulmonary infection, the implementation of a personalized hemodynamic optimization strategy based on a systematic preload evaluation, did not significantly improve early organ dysfunction measured by SOFA score. However, this personalized strategy led to a meaningful reduction in the mean ICU length of stay, without increasing mortality.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eNone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eOH, XC and EV conceived, designed the study, and obtained funding for the study. All authors oversaw trial conduction and study management; they equally contributed to data acquisition. OH, XC and EV drafted the manuscript. OH, XC, BM and EV directly accessed and verified the data. OH, XC, BM and EV conducted the analysis and interpreted the data. All authors critically revised and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThe GOAL study was publicly funded by the French Ministry of Health (PHRC-n, n\u0026deg;17-0016). The funder had no role in the study design, study conduction, data analysis, data interpretation, or writing of the report. Brest university hospital is the sponsor of the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eThe dataset and data dictionary were accessible upon request. A de-identified participant dataset could be requested from the corresponding author for consideration. Access to the dataset for scientific purposes may then be granted following a review.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u0026nbsp;\u003c/strong\u003eOH reports honoraria from Edwards Life Science for lectures. AH reports honoraria from Edwards Life Science, LFB and Octapharma. ML reports honoraria from Edwards Life Science, Shionogi and Grifols, and consulting fees from Viatris and AOP. KA reports honoraria from Vygon, LFB and Baxter. EV reports consulting fees from Abbott and Coloplast. Other authors report no conflict of interest related to this publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval:\u003c/strong\u003e The study was approved by the French Ethics Central Committee (number: 18.07.09.57456).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate and consent to publish:\u003c/strong\u003e Written informed consent was obtained from all patients or their legal surrogates until patients were able to consent at all sites.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, Colombara DV, Ikuta KS, Kissoon N, Finfer S, Fleischmann-Struzek C, Machado FR, Reinhart KK, Rowan K, Seymour CW, Watson RS, West TE, Marinho F, Hay SI, Lozano R, Lopez AD, Angus DC, Murray CJL, Naghavi M (2020) Global, regional, and national sepsis incidence and mortality, 1990\u0026ndash;2017: analysis for the Global Burden of Disease Study. Lancet 395:200\u0026ndash;211\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVincent J-L, De Backer D (2013) Circulatory Shock. N Engl J Med 369:1726\u0026ndash;1734\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEvans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, Mcintyre L, Ostermann M, Prescott HC, Schorr C, Simpson S, Wiersinga WJ, Alshamsi F, Angus DC, Arabi Y, Azevedo L, Beale R, Beilman G, Belley-Cote E, Burry L, Cecconi M, Centofanti J, Coz Yataco A, De Waele J, Dellinger RP, Doi K, Du B, Estenssoro E, Ferrer R, Gomersall C, Hodgson C, M\u0026oslash;ller MH, Iwashyna T, Jacob S, Kleinpell R, Klompas M, Koh Y, Kumar A, Kwizera A, Lobo S, Masur H, McGloughlin S, Mehta S, Mehta Y, Mer M, Nunnally M, Oczkowski S, Osborn T, Papathanassoglou E, Perner A, Puskarich M, Roberts J, Schweickert W, Seckel M, Sevransky J, Sprung CL, Welte T, Zimmerman J, Levy M, Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, Mcintyre L, Ostermann M, Prescott HC, Schorr C, Simpson S, Wiersinga WJ, Alshamsi F, Angus DC, Arabi Y, Azevedo L, Beale R, Beilman G, Belley-Cote E, Burry L, Cecconi M, Centofanti J, Coz Yataco A, De Waele J, Dellinger RP, Doi K, Du B, Estenssoro E, Ferrer R, Gomersall C, Hodgson C, M\u0026oslash;ller MH, Iwashyna T, Jacob S, Kleinpell R, Klompas M, Koh Y, Kumar A, Kwizera A, Lobo S, Masur H, McGloughlin S, Mehta S, Mehta Y, Mer M, Nunnally M, Oczkowski S, Osborn T, Papathanassoglou E, Perner A, Puskarich M, Roberts J, Schweickert W, Seckel M, Sevransky J, Sprung CL, Welte T, Zimmerman J, Levy M (2021-10-02) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med 2021 47:1147\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSakr Y, Rubatto Birri PN, Kotfis K, Nanchal R, Shah B, Kluge S, Schroeder ME, Marshall JC, Vincent J-L, Intensive Care Over Nations I (2017) Higher Fluid Balance Increases the Risk of Death From Sepsis: Results From a Large International Audit. Crit Care Med 45:386\u0026ndash;394\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMarik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D (2017) Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med : 1\u0026ndash;8\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChapalain X, Vermeersch V, Egreteau P-Y, Prat G, Alavi Z, Vicaut E, Huet O (2019) Association between fluid overload and SOFA score kinetics in septic shock patients: a retrospective multicenter study. J Intensive Care 7:42\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThe National Heart L, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network (2023) Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med 388:499\u0026ndash;510\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMeyhoff TS, Hjortrup PB, Wetterslev J, Sivapalan P, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain M, Pettil\u0026auml; V, M\u0026oslash;ller MH, Kj\u0026aelig;r M-BN, Lange T, Overgaard-Steensen C, Brand BA, Winther-Olesen M, White JO, Quist L, Westergaard B, Jonsson AB, Hjorts\u0026oslash; CJS, Meier N, Jensen TS, Engstr\u0026oslash;m J, Nebrich L, Andersen-Ranberg NC, Jensen JV, Joseph NA, Poulsen LM, Herl\u0026oslash;v LS, S\u0026oslash;lling CG, Pedersen SK, Knudsen KK, Straarup TS, Vang ML, Bundgaard H, Rasmussen BS, Aagaard SR, Hildebrandt T, Russell L, Bestle MH, Sch\u0026oslash;nemann-Lund M, Br\u0026oslash;chner AC, Elvander CF, Hoffmann SKL, Rasmussen ML, Martin YK, Friberg FF, Seter H, Aslam TN, \u0026Aring;dn\u0026oslash;y S, Seidel P, Strand K, Johnstad B, Joelsson-Alm E, Christensen J, Ahlstedt C, Pfortmueller CA, Siegemund M, Greco M, Raděj J, Kř\u0026iacute;ž M, Gould DW, Rowan KM, Mouncey PR, Perner A (2022) Restriction of Intravenous Fluid in ICU Patients with Septic Shock. New England Journal of Medicine 386: 2459\u0026ndash;2470\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGuyton Arthur C (1968) /03/01) Regulation of Cardiac Output. Anesthesiology 29\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMessina A, Calabr\u0026ograve; L, Pugliese L, Lulja A, Sopuch A, Rosalba D, Morenghi E, Hernandez G, Monnet X, Cecconi M (2022) Fluid challenge in critically ill patients receiving haemodynamic monitoring: a systematic review and comparison of two decades. Crit Care 26:186\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCecconi M, Aya HD, Geisen M, Ebm C, Fletcher N, Grounds RM, Rhodes A, Cecconi M, Aya HD, Geisen M, Ebm C, Fletcher N, Grounds RM, Rhodes A (2013) (2013-05-08) Changes in the mean systemic filling pressure during a fluid challenge in postsurgical intensive care patients. Intensive Care Med 39:739\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRichard J-C, Bayle F, Bourdin G, Leray V, Debord S, Delannoy B, Stoian AC, Wallet F, Yonis H, Guerin C (2015) Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Crit Care 19:5\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen C, Kollef MH (2015) Targeted fluid minimization following initial resuscitation in septic shock: A pilot study. Chest 148:1462\u0026ndash;1469\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDouglas IS, Alapat PM, Corl KA, Exline MC, Forni LG, Holder AL, Kaufman DA, Khan A, Levy MM, Martin GS, Sahatjian JA, Seeley E, Self WH, Weingarten JA, Williams M, Hansell DM (2020) Fluid Response Evaluation in Sepsis Hypotension and Shock: A Randomized Clinical Trial. Chest 158:1431\u0026ndash;1445\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSinger M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche J-D, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent J-L, Angus DC (2016) The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315:801\u0026ndash;810\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMonnet X, Anguel N, Naudin B, Jabot J, Richard C, Teboul J-L (2010) Arterial pressure-based cardiac output in septic patients: different accuracy of pulse contour and uncalibrated pressure waveform devices. Crit Care 14:R109\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMuller L, Toumi M, Bousquet P-J, Riu-Poulenc B, Louart G, Candela D, Zoric L, Suehs C, de La Coussaye J-E, Molinari N, Lefrant J-Y, AzuR\u0026eacute;a G (2011) An increase in aortic blood flow after an infusion of 100 ml colloid over 1 minute can predict fluid responsiveness: the mini-fluid challenge study. Anesthesiology 115:541\u0026ndash;547\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMallat J, Meddour M, Durville E, Lemyze M, Pepy F, Temime J, Vangrunderbeeck N, Tronchon L, Thevenin D, Tavernier B (2015) Decrease in pulse pressure and stroke volume variations after mini-fluid challenge accurately predicts fluid responsiveness. British Journal of Anaesthesia: aev222\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVincent JL, Moreno R, Takala J, Willatts S, De Mendon\u0026ccedil;a A, Bruining H, Reinhart CK, Suter PM, Thijs LG (1996) The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 22:707\u0026ndash;710\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHemming K, Haines TP, Chilton PJ, Girling AJ, Lilford RJ (2015) -02-06) The stepped wedge cluster randomised trial: rationale, design, analysis, and reporting. BMJ 350:h391\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSivapalan P, Ellekjaer KL, Jessen MK, Meyhoff TS, Cronhjort M, Hjortrup PB, Wetterslev J, Granholm A, M\u0026oslash;ller MH, Perner A (2023) Lower vs Higher Fluid Volumes in Adult Patients With Sepsis: An Updated Systematic Review With Meta-Analysis and Trial Sequential Analysis. Chest 164:892\u0026ndash;912\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcMullan RR, McAuley DF, O\u0026rsquo;Kane CM, Silversides JA (2024) Vascular leak in sepsis: physiological basis and potential therapeutic advances. Crit Care 28:97\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMessina A, Dell\u0026rsquo;Anna A, Baggiani M, Torrini F, Maresca GM, Bennett V, Saderi L, Sotgiu G, Antonelli M, Cecconi M (2019) Functional hemodynamic tests: a systematic review and a metanalysis on the reliability of the end-expiratory occlusion test and of the mini-fluid challenge in predicting fluid responsiveness. Crit Care 23:264\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Septic shock, Hemodynamic, Fluid therapy, Personalized medicine","lastPublishedDoi":"10.21203/rs.3.rs-7826002/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7826002/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eTreatment of circulatory failure involves fluid and/or catecholamines infusion. Excessive fluid infusion is associated with worse outcomes, while restrictive fluid strategies show no significant benefits. We aimed to evaluate efficacy of a personalized hemodynamic optimization protocol including three pillars: (i) diagnosing acute circulatory failure, (ii) using a validated hemodynamic monitoring, and (iii) evaluating preload dependency state before any fluid resuscitation.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eMulticenter, stepped-wedge, cluster-randomized trial involving adult patients with septic shock due to an abdominal or a pulmonary infection. Patients received either usual care (control period), or a personalized hemodynamic optimization strategy (intervention period). Hierarchized primary outcomes included delta SOFA (Sepsis-related Organ Failure Assessment) score from inclusion to day 5, ICU length of stay, hospital length of stay, ventilator-free days, renal failure-free days and catecholamine-free days.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003e517 patients were enrolled: 289 in the control group and 228 in the intervention group. Delta SOFA score was 2.4 in the control group and 1.8 in the intervention group (p\u0026thinsp;=\u0026thinsp;0.41). ICU length of stay was reduced by 2.5 days (95% CI 0 to 5) in the intervention group. In overall population, other primary outcomes showed no differences. For severe patients (i.e., baseline SOFA\u0026thinsp;\u0026ge;\u0026thinsp;10), ICU and hospital stay length of stay was also reduced by 3.7 days (95% CI -0.4 to 7.8) and 6.9 days (95% CI -0.7 to 14.4), respectively.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eAlthough no statistically significant difference was observed in delta SOFA score, a personalized hemodynamic optimization strategy reduced ICU length of stay.\u003c/p\u003e\u003ch2\u003eTrial Registration\u003c/h2\u003e\u003cp\u003eClinicalTrials.gov Identifier NCT03461900\u003c/p\u003e","manuscriptTitle":"Effect of a personalized hemodynamic optimization strategy during septic shock: a stepped-wedge, cluster-randomized, open-label, controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-27 14:25:40","doi":"10.21203/rs.3.rs-7826002/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"24900524-97f9-4337-957c-14f98cab69f2","owner":[],"postedDate":"October 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-02T16:24:54+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-27 14:25:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7826002","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7826002","identity":"rs-7826002","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}