Association of active fluid de-escalation timing with clinical outcomes in patients with septic shock: a multicenter cohort study

Association of active fluid de-escalation timing with clinical outcomes in patients with septic shock: a multicenter cohort study | 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 Association of active fluid de-escalation timing with clinical outcomes in patients with septic shock: a multicenter cohort study Ruoyu Zhuang, Rui Tian, Ruoming Tan, Danfeng Dong, Yunzhe Wu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8247207/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Jan, 2026 Read the published version in BMC Infectious Diseases → Version 1 posted 10 You are reading this latest preprint version Abstract Background Early fluid resuscitation is a basic therapy for patients with septic shock but may lead to fluid overload associated with poor clinical outcomes. Active de-escalation (accumulated fluid removal using diuretics or ultrafiltration) is a crucial part of fluid management. Methods In this retrospective cohort study, patients were classified as the early group (with septic shock receiving active de-escalation within 24 hours after hemodynamic stability) and late group. The primary outcome was 28-day mortality. Secondary outcomes included use of mechanical ventilation and renal replacement therapy, incidence of kidney injury and hemodynamic deterioration. Landmark analysis and restricted cubic splines based on Cox regression were performed. Results A total of 5,782 patients were included, with 3,255 cases underwent de-escalation within 24 hours after hemodynamic stability and 1,898 pairs of patients were matched after propensity score matching. Patients in the early group were found with lower 28-day mortality (12.6% vs. 18.0%, P < 0.001), more weaning from mechanical ventilation (32.5% vs. 56.2%, P < 0.001), lower incidence of AKI (14.6% vs.17.1%, P = 0.046) and hemodynamic deterioration (11.4 vs. 16%, P < 0.001) on day 3. Similar outcomes were observed on day 5. A U-shaped association between fluid balance and 28-day mortality was observed. Daily fluid balance of − 1482mL within 3 days is associated with the lowest HR for 28-day mortality and range from − 2814mL to − 445mL represents HR lower than 1 for 28-day mortality. Conclusions Early de-escalation was associated with improved prognosis for patients with septic shock and fluid overload. Maintaining fluid balance in an optimal range could be beneficial and a de-escalation strategy according to fluid balance is recommended. Clinical Trial Number: Not applicable De-escalation Septic shock Fluid therapy Timing Clinical outcomes Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Sepsis was a systemic inflammatory response to infection and septic shock was described as sepsis complicated by either hypotension or hyperlactatemia which could be refractory to fluid resuscitation[1]. Large volumes of fluid resuscitation are recommended for patients with septic shock to improve cardiac output and limit progression to multiple organ dysfunction and death[2]. The maladaptive excess of fluid volume having adverse effects on organ function is termed “fluid accumulation syndrome”[3]. While early goal-directed therapy (EGDT) revolutionized sepsis care by emphasizing rapid crystalloid infusion to restore perfusion, mounting evidence highlights detrimental effects of excessive fluid accumulation, including tissue oedema, impaired organ function, and increased mortality[4–7]. Thus, fluid management in sepsis has evolved from a one-size-fits-all aggressive resuscitation approach to a dynamic, phased strategy that balances early hemodynamic stability with prevention of fluid overload[8]. This paradigm shift underscores the critical need for active fluid de-escalation after initial resuscitation to mitigate iatrogenic harm. The conceptual ROSE model summarizes 4 dynamic fluid phases (resuscitation, optimization, stabilization and evacuation) to maximize benefits and minimize harms in fluid therapy[9]. To achieve the goals of fluid management, we must answer 4 questions (when to start or to stop fluid therapy, and when to start or to stop fluid removal)[10]. However, current studies and guidelines focus on the initial resuscitation but fail to provide more information on fluid removal[11, 12]. Therefore, it is necessary to assess the appropriate timing and extent of fluid removal. The term “de-escalation” refers to active removal of accumulated fluid in patients with fluid overload using drugs and/or ultrafiltration (UF)[13]. Randomized clinical trial showed that conservative fluid administration and active fluid removal was feasible to reduce fluid overload compared to usual care[14]. Meanwhile, negative fluid balance was furtherly reported associated with improved outcomes[5]. However, it remains unclear referring optimal strategy of active fluid de-escalation (timing, type, dose and mode of fluid removal, combination therapy, monitoring, duration, and discontinuation)[15]. Thus, we undertook a large-scale multicenter retrospective cohort study of patients with septic shock by using data from the Medical Information Mart for Intensive Care IV database (MIMIC-IV), aiming to help us understand the indications, approaches, endpoints, and effects of de-escalation. Methods Study design This retrospective cohort study was based on MIMIC-IV database Version 2.2 (MIMIC-IV v2.2) using Structured Query Language (SQL). The study was conducted following Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines[16]. Population selection All patients with septic shock recognized within 24 hours on ICU admission and eligible for de-escalation were included in main analysis. Definition of sepsis was according to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)[17]. Recognition of shock included using vasopressor, or serum lactate (Lac) ≥ 2mmol/L, or mean arterial pressure (MAP) < 65mmHg. Patients were eligible for de-escalation if they achieved hemodynamic stability (with a cumulative fluid balance over 2000 mL from admission, an equivalent dose of norepinephrine lower than 0.2µg/kg·min − 1 , Lac < 2mmol/L and MAP ≥ 65mmHg as well)[14]. Administration of diuretics or ultrafiltration after hemodynamic stability was defined as an act of de-escalation. Patients diagnosed with hypovolemic shock, subarachnoid hemorrhage, diabetic ketoacidosis, chronic kidney disease and pregnancy were excluded[14]. Records without necessary data were also excluded. We excluded those with ICU stays less than 24h or those with de-escalation before hemodynamic stability. Only the first ICU stay were included in analysis. Patients eligible for de-escalation yet without records of active de-escalation were analyzed prior to our main analysis. We then grouped the main analysis cohort into two groups according to hours from hemodynamic stability to the time of de-escalation, of which median value was 21.18 hours (e-Figure 1) . Early de-escalation group included patients with de-escalation within 24 hours after hemodynamic stability. Late de-escalation group included the rest. Variables and outcomes Demographics, comorbidities, fluid administration, severity of illness, cumulative fluid balance, renal replacement therapy (RRT) and mechanical ventilation (MV) administration on Day 1 of hemodynamic stability were gathered. The primary outcome was 28-day all-cause mortality from hemodynamic stability. Secondary outcomes included administration of MV and RRT, kidney injury and hemodynamic deterioration on Day 3 and Day 5 after enrollment. Hemodynamic deterioration was recognized as higher equivalent dose vasopressors, or newly vasopressor administration after enrollment. Daily and accumulated fluid balance within 3 days after hemodynamic stability were also collected. Study Day 1 was a period of 24 hours after enrollment and subsequent study days were consecutive 24-hour periods. Fluid balance was the total delivered input (intravenous medications, fluid boluses, blood products, enteral and parenteral nutrition, and maintenance) minus total measured output (urine, ultrafiltrate, surgical drains) as recorded. Statistical analysis Skewed continuous variables were presented as medians with interquartile ranges (IQRs) and were compared using Wilcoxon rank-sum test. Categorial variables were presented as counts and percentages and were compared using Chi-square test or Fisher’s exact test. Pre-defined confounders included Charlson comorbidity index (CCI), number of infection sites, whether admitted from emergency department, age, gender, ethnicity, and colloid administration, albumin administration, Sequential Organ Failure Assessment (SOFA) score, acute kidney injury (AKI), MV use, and cumulative fluid balance till hemodynamic stability. Association of de-escalation and 28-day mortality was analyzed using univariable and multivariable logistic regression priorly. The multivariable regression model was adjusted for the pre-defined confounders. Variables with > 30% missing values were excluded to minimize the bias, and the other were processed using multiple imputation method. The cohort for main analysis were then furtherly processed through propensity score matching (PSM). PSM was applied with a caliper width of 0.02 to mitigate baseline imbalances and paired in a 1:1 ratio using the nearest neighbor matching technique for pre-defined confounders. The efficacy of PSM was evaluated by the standardized mean difference (SMD) with an SMD < 0.1 indicating a balanced model. Kaplan-Meier method with log-rank test and landmark analysis were used to illustrate survival for 28 days after hemodynamic stability. Potential nonlinear association of fluid balance after hemodynamic stability with 28-day all-cause mortality was then demonstrated using restricted cubic splines (RCS) with five knots located at the 5th, 35th, 50th, 65th, and 95th percentiles based on Cox regression. Subgroup analysis for primary outcome was conducted for: (1) ≥ 65-year vs. < 65-year ; (2) SOFA score ≥ 6 vs. < 6; (3) Lactate ≥ 4mmol/L vs. < 4mmol/L; (4) with vs. without MV on Day 1 of enrollment; (5) with vs. without heart failure; (6) with vs. without urinary infection; (7) with vs. without blood infection; (8) with vs. without abdominal infection; (9) with vs. without pneumonia. Statistical analysis and plotting were constructed using R Statistical Software (v4.4.3; R Core Team 2025) and GraphPad Prism version 10.4.1 for Mac OS X (GraphPad Software, Boston, Massachusetts USA). Statistical significance was represented as P < 0.05 for two-sided hypothesis. Data access Contemporary electronic health records and all personal information in MIMIC-IV database have been de-identified, so that patient consent and ethical approval was waived. Data extraction was conducted by the researcher (TW) through qualified access (Certificate No.33461595). Results Patient Characteristics This cohort study included 10,907 patients with septic shock who met the inclusion criteria, among whom 5,782 had records of de-escalation after enrollment. De-escalation after hemodynamic stability was affirmed associated with decreased 28-day mortality by logistic regression model ( e- Table 1 ). Median time of 21.18 hours from hemodynamic stability to de-escalation was showed in distribution density plot (e-Figure 1) . Therefore, we set 24 hours as the cut-off time for grouping to better meet clinical needs, 3,255 cases underwent de-escalation within 24 hours and 2,527 cases after 24 hours. 1,898 pairs of patients were matched after PSM (Fig. 1 ). Clinical information in both groups before and after PSM is presented in Table 1 . Patients in late group were found with higher SOFA scores (7 [5 to 9] vs. 6 [4 to 8]), more AKI incidence (33.3% vs. 27.8%) and emergency room admission (87.3 vs. 70%) before PSM. Furthermore, patients in early group had a higher cumulative fluid balance till hemodynamic stability (2,875 [2,335 to 3,750] vs. 2,573 [2,223 to 3,500]) and received more colloids (67% vs. 49%). Nevertheless, no statistically significant differences were observed between two groups in CCI ( P = 0.924) or age ( P = 0.915). The imbalance was minimized after PSM. Table 1 Baseline characteristics of the patients before and after PSM. Before PSM After PSM Characteristics Overall (N = 5782) De-escalation after 24h (N = 2527) De-escalation within 24h (N = 3255) P -value Overall (N = 3796) De-escalation after 24h (N = 1898) De-escalation within 24h (N = 1898) P -value Demographic Age, yrs, median [IQR] 68 [59, 78] 67 [56, 78] 69 [60, 78] < 0.001 68 [58, 78] 68 [57, 79] 68 [59, 77] 0.915 Gender, n (%) < 0.001 0.895 Female 2268 (39.2) 1090 (43.1) 1178 (36.2) 1533 (40.4) 764 (40.3) 769 (40.5) Male 3514 (60.8) 1437 (56.9) 2077 (63.8) 2263 (59.6) 1134 (59.7) 1129 (59.5) Ethnicity, n (%) < 0.001 0.329 White 4017 (69.5) 1666 (65.9) 2351 (72.2) 2584 (68.1) 1288 (67.9) 1296 (68.3) Black 336 (5.8) 179 (7.1) 157 (4.8) 230 (6.1) 125 (6.6) 105 (5.5) Asian 143 (2.5) 63 (2.5) 80 (2.5) 91 (2.4) 42 (2.2) 49 (2.6) Latino 156 (2.7) 66 (2.6) 90 (2.8) 103 (2.7) 44 (2.3) 59 (3.1) Others 1130 (19.5) 553 (21.9) 577 (17.7) 788 (20.8) 399 (21.0) 389 (20.5) Admitted to ER, n (%) 4484 (77.6) 2206 (87.3) 2278 (70.0) < 0.001 3219 (84.8) 1601 (84.4) 1618 (85.2) 0.470 Comorbidities CCI, median [IQR] 4 [3, 6] 5 [3, 7] 4 [3, 6] 0.924 5 [3, 7] 5 [3, 7] 5.00 [3, 7] 0.534 Myocardial infarct, n (%) 1231 (21.3) 440 (17.4) 791 (24.3) < 0.001 850 (22.4) 355 (18.7) 495 (26.1) < 0.001 Congestive heart failure, n (%) 1719 (29.7) 660 (26.1) 1059 (32.5) < 0.001 1185 (31.2) 513 (27.0) 672 (35.4) < 0.001 Peripheral vascular disease, n (%) 900 (15.6) 339 (13.4) 561 (17.2) < 0.001 594 (15.6) 274 (14.4) 320 (16.9) 0.044 Cerebrovascular disease, n (%) 715 (12.4) 368 (14.6) 347 (10.7) < 0.001 491 (12.9) 276 (14.5) 215 (11.3) 0.004 Dementia, n (%) 135 (2.3) 88 (3.5) 47 (1.4) < 0.001 92 (2.4) 57 (3.0) 35 (1.8) 0.027 Chronic pulmonary disease, n (%) 1532 (26.5) 675 (26.7) 857 (26.3) 0.766 1039 (27.4) 512 (27.0) 527 (27.8) 0.610 Rheumatic disease, n (%) 218 (3.8) 104 (4.1) 114 (3.5) 0.252 145 (3.8) 76 (4.0) 69 (3.6) 0.611 Peptic ulcer disease, n (%) 139 (2.4) 89 (3.5) 50 (1.5) < 0.001 102 (2.7) 62 (3.3) 40 (2.1) 0.035 Liver disease, n (%) 1066 (18.4) 599 (23.7) 467 (14.3) < 0.001 486 (12.8) 279 (14.7) 207 (10.9) < 0.001 Diabetes, n (%) 1810 (31.3) 687 (27.2) 1123 (34.5) < 0.001 1163 (30.6) 516 (27.2) 647 (34.1) < 0.001 Paraplegia, n (%) 198 (3.4) 127 (5.0) 71 (2.2) < 0.001 143 (3.8) 89 (4.7) 54 (2.8) 0.004 Malignant cancer, n (%) 524 (9.1) 295 (11.7) 229 (7.0) < 0.001 376 (9.9) 212 (11.2) 164 (8.6) 0.011 Severe liver disease, n (%) 259 (4.5) 165 (6.5) 94 (2.9) < 0.001 193 (5.1) 120 (6.3) 73 (3.8) < 0.001 Metastatic solid tumor, n (%) 201 (3.5) 136 (5.4) 65 (2.0) < 0.001 154 (4.1) 101 (5.3) 53 (2.8) < 0.001 Source of infection Upper respiratory infection, n (%) 439 (7.6) 274 (10.8) 165 (5.1) < 0.001 297 (7.8) 144 (7.6) 153 (8.1) 0.629 Pneumonia, n (%) 802 (13.9) 506 (20.0) 296 (9.1) < 0.001 572 (15.1) 297 (15.6) 275 (14.5) 0.341 Abdominal infection, n (%) 326 (5.6) 220 (8.7) 106 (3.3) < 0.001 217 (5.7) 116 (6.1) 101 (5.3) 0.328 Urinary infection, n (%) 777 (13.4) 437 (17.3) 340 (10.4) < 0.001 551 (14.5) 244 (12.9) 307 (16.2) 0.004 Blood infection, n (%) 1251 (21.6) 830 (32.8) 421 (12.9) < 0.001 891 (23.5) 489 (25.8) 402 (21.2) 0.001 Soft tissue infection, n (%) 45 (0.8) 38 (1.5) 7 (0.2) < 0.001 41 (1.1) 23 (1.2) 18 (0.9) 0.530 CNS infection, n (%) 279 (4.8) 175 (6.9) 104 (3.2) < 0.001 31 (0.8) 24 (1.3) 7 (0.4) 0.004 Other infection, n (%) 45 (0.8) 38 (1.5) 7 (0.2) < 0.001 185 (4.9) 87 (4.6) 98 (5.2) 0.451 Number of infection sites, n (%) < 0.001 0.018 No specific site 3320 (57.4) 1012 (40.0) 2308 (70.9) 1985 (52.3) 950 (50.1) 1035 (54.5) 1 1345 (23.3) 789 (31.2) 556 (17.1) 1062 (28.0) 579 (30.5) 483 (25.4) 2 794 (13.7) 503 (19.9) 291 (8.9) 562 (14.8) 281 (14.8) 281 (14.8) 3 248 (4.3) 166 (6.6) 82 (2.5) 152 (4.0) 70 (3.7) 82 (4.3) 4 68 (1.2) 53 (2.1) 15 (0.5) 32 (0.8) 17 (0.9) 15 (0.8) 5 6 (0.1) 3 (0.1) 3 (0.1) 3 (0.1) 1 (0.1) 2 (0.1) Characteristics on Day 1 of hemodynamic stability SOFA score on Day 1 of hemodynamic stability median [IQR] 6 [5, 9] 7 [5, 9] 6 [4, 8] < 0.001 6 [5, 9] 7 [5, 9] 6 [5, 9] 0.337 Ventilation on Day 1 of hemodynamic stability, n (%) 4668 (80.7) 2080 (82.3) 2588 (79.5) 0.008 3068 (80.8) 1546 (81.5) 1522 (80.2) 0.343 AKI on Day 1 of hemodynamic stability, n (%) 1747 (30.2) 841 (33.3) 906 (27.8) < 0.001 1254 (33.0) 628 (33.1) 626 (33.0) 0.973 Accumulated fluid balance on Day 1 of hemodynamic stability, mL, median [IQR] 2726 [2285, 3700] 2573 [2223, 3500] 2875 [2335, 3750] < 0.001 2630 [2253, 3555] 2597 [2239, 3500] 2676 [2273, 3600] 0.030 Categories of fluid administered before hemodynamic stability Crystalloid, n (%) 5619 (97.2) 2448 (96.9) 3171 (97.4) 0.245 3672 (96.7) 1840 (96.9) 1832 (96.5) 0.523 Colloid, n (%) 3417 (59.1) 1237 (49.0) 2180 (67.0) < 0.001 2031 (53.5) 1028 (54.2) 1003 (52.8) 0.435 Nutrient, n (%) 435 (7.5) 196 (7.8) 239 (7.3) 0.588 308 (8.1) 148 (7.8) 160 (8.4) 0.513 Albumin, n (%) 615 (10.6) 280 (11.1) 335 (10.3) 0.357 408 (10.7) 197 (10.4) 211 (11.1) 0.496 PSM: Propensity Score Matching; ER: Emergency Room; CCI: Charlson Comorbidity Index; CNS: Central Nervous System; SOFA: Sequential Organ Failure Assessment; AKI: Acute Kidney Injury; IQR: Interquartile Range. Primary outcome The 28-day mortality for patients from early de-escalation group was lower than that observed in late group (12.6% vs. 18.0%, P < 0.001) (Table 2 ). The Kaplan–Meier survival analysis for 28-day survival is illustrated in Fig. 2 . In 7-day landmark analysis of matched population, the survival rate of early group was similar to that of late group ( P = 0.428); however, the 28-day mortality of early group was lower than that in late group (log-rank P < 0.001). Table 2 Primary and secondary outcomes. Outcomes Overall (N = 3796) De-escalation after 24h (N = 1898) De-escalation within 24h (N = 1898) P -value Primary outcome 28-day all-cause mortality, n (%) 580 (15.3) 341 (18.0) 239 (12.6) < 0.001 Secondary outcome MV administration and weaning Duration of MV, hours, median [IQR] 24.50 [10.70, 117.00] 60.50 [14.85, 170.00] 17.00 [8.91, 61.47] < 0.001 Duration of MV after hemodynamic stability, hours, median [IQR] 8.66 [0.00, 67.60] 17.20 [0.00, 111.25] 5.59 [0.00, 25.70] < 0.001 Use of MV on Day 3 after hemodynamic stability, n (%) 1455 (38.3) 980 (51.6) 475 (25.0) < 0.001 Deterioration of patients with MV on Day 3 after hemodynamic stability, n (%) 70 (1.8) 50 (2.6) 20 (1.1) < 0.001 Weaning from MV on Day 3 after hemodynamic stability, n (%) 1683 (44.3) 616 (32.5) 1067 (56.2) < 0.001 Use of MV on Day 5 after hemodynamic stability, n (%) 483 (12.7) 303 (16.0) 180 (9.5) < 0.001 Deterioration of patients with MV on Day 5 after hemodynamic stability, n (%) 25 (0.7) 18 (0.9) 7 (0.4) 0.045 Weaning from MV on Day 5 after hemodynamic, n (%) 2610 (68.8) 1261 (66.4) 1349 (71.1) 0.002 RRT administration and AKI Use of RRT on Day 3 after hemodynamic stability, n (%) 149 (3.9) 62 (3.3) 87 (4.6) 0.045 Kidney injury on Day 3 after hemodynamic stability, n (%) 602 (15.9) 324 (17.1) 278 (14.6) 0.046 Use of RRT on Day 5 after hemodynamic stability, n (%) 120 (3.2) 48 (2.5) 72 (3.8) 0.033 Kidney injury on Day 5 after hemodynamic stability, n (%) 431 (11.4) 220 (11.6) 211 (11.1) 0.682 Shock Hemodynamic deterioration on Day 3 after hemodynamic stability, n (%) 520 (13.7) 304 (16.0) 216 (11.4) < 0.001 Hemodynamic deterioration on Day 5 after hemodynamic stability, n (%) 534 (14.1) 311 (16.4) 223 (11.7) < 0.001 RRT: Renal Replacement Therapy; MV: Mechanical Ventilation; AKI: Acute Kidney Injury; SOFA: Sequential Organ Failure Assessment; IQR: Interquartile Range. Secondary outcomes There were differences between early de-escalation group and late group with statistical significance in terms of MV and RRT administration, kidney injury and hemodynamic deterioration in the matched cohort (Table 2 ). Patients in early group had a shorter duration of MV during ICU stay (17.00 [8.91 to 61.47] vs.60.50 [14.85 to 170.00], P < 0.001) and after hemodynamic stability (5.59 [0.00 to 25.70] vs. 17.20 [0.00 to 111.25], P < 0.001). On day 3, we found less use of MV (25% vs. 51.6%, P < 0.001), less deterioration among the patients who received MV (1.1 vs.2.6%, P < 0.001) and more weaning from MV (56.2% vs.32.5%, P < 0.001) in early de-escalation group. Meanwhile, lower incidence of AKI (14.6% vs.17.1%, P = 0.046) and less hemodynamic deterioration (11.4% vs. 16%, P < 0.001) were observed in early group on day 3. On day 5, similar outcomes were also observed in both MV administration and hemodynamic deterioration, while there was no statistically significant difference in terms of kidney injury. Fluid balance and clinical outcomes Fluid balance over time is shown in e- Table 2 . Patients in early group had a lower daily fluid balance than those in late group within 3 days after hemodynamic stability (− 770 [− 1604 to 2] vs. −29 [− 842 to 993], P < 0.001). Cumulative fluid balance was lower in early group on day 2 and day 3. Lower fluid balance was observed in survivors than in non-survivors (Fig. 3 ). To more clearly elucidate the relationship between fluid balance and the risk of 28-day all-cause mortality, we performed RCS analysis on the total population ( e-Figure 2 ) and the population after PSM (Fig. 4 ). RCS model revealed a U-shaped connection between fluid balance within 3 days after hemodynamic stability and 28-day all-cause mortality ( P for non-linear < 0.001). Daily fluid balance of − 1482mL and accumulated fluid balance within 3 days of − 4446mL are associated with the lowest HR for 28-day all-cause mortality, respectively. Daily fluid balance between − 2814mL and − 445mL and accumulated fluid balance within 3 days between − 8443mL and − 1337mL were associated with HR for 28-day all-cause mortality lower than 1, respectively. Subgroup analyses Consistent association between early active de-escalation and lower 28-day all-cause mortality in patients with septic shock was found through subgroup analyses. For patients with lac ≥ 4 mmol/L, AKI, blood infection, abdominal infection and pneumonia, this correlation was not statistically significant ( e-Figure 3 ). Discussion Earlier resuscitation is core to maintaining primary hemodynamic stability, restoring tissue perfusion and oxygenation associated with reduced mortality in patients with sepsis[18, 19]. However, large fluid volume results in severe tissue oedema and increased interstitial fluid in vital organs leading to endothelial injury and impaired oxygen and metabolite diffusion[20]. Moreover, observational studies demonstrate the association between fluid overload and adverse outcomes such as higher mortality and prolonged MV support in critical illness states[4, 5, 21, 22]. Despite growing evidence opposing excessively positive fluid balance, fluid overload remains common in ICU patients. Two complementary strategies have evolved to address the issue of fluid overload: restrictive fluid administration or active fluid de-resuscitation (de-escalation)[5]. A restrictive fluid resuscitation approach has been investigated while several randomized trials observed no significant benefits for patients with septic shock[23, 24]. POINCARE-2 conservative strategy did not reduce 60-day mortality in a recent stepped wedge cluster open‑label randomized controlled trial. Actual exposure to fluid removal strategy might not be reflected and further analyses required[25]. Another approach is de-escalation therapy, which actively removes excess fluid through diuretics and/or ultrafiltration[13]. Negative fluid balance achieved by active de-escalation was reported associated with improved outcomes[5]. Similarly, we found that de-escalation within 24 hours after hemodynamic stability yielded better results in terms of 28-day mortality, MV administration, AKI incidence and hemodynamic changes. Another study also found latent decreasing fluid balance trajectory in patients associated with a decreased risk of hospital mortality and major adverse kidney events (MAKE) in critically ill patients with septic shock[26]. Thus, de-escalation can directly affect the fluid balance trajectory in patients with fluid overload. However, current studies and guidelines cannot answer when to start or to stop fluid removal[2, 27]. To answer the question about when to start de-escalation, we conducted the following research. We selected patients with septic shock and fluid balance over 2000 ml with an equivalent dose of norepinephrine lower than 0.2µg/kg·min − 1 to start de-escalation according to the RADAR-2 study[14]. Interestingly, we found that the median de-escalation time for these patients was 21.18 hours, yet distribution of the cohort was obviously biased when grouped by other timepoints such as 6 hours, 12 hours. Therefore, we set 24 hours after hemodynamic stability as a critical timepoint, which is helpful for clinicians to make decisions. Furtherly, clinicians should consider multiple factors when assessing fluid overload and hemodynamic stability. This requires prospective clinical data (e.g., imaging studies) as well as dynamic monitoring of brain natriuretic peptide and urine output changes. Although the 24-hour grouping predicted outcomes differently, this specific timepoint was chosen artificially and might not be the best marker for deciding when to de-escalate treatment. Future studies should use personalized data to develop models that predict the best timing. Additionally, since responses to diuretics and RRT vary greatly among individuals, more research is needed to optimize de-escalation strategies[28, 29]. To answer the question about when to stop fluid de-escalation, we need to find the association between volume of de-escalation and clinical outcomes. Woodward et al. used cubic spline to find a potentially U-shaped nonlinear relation between fluid overload and MAKE in critically ill patients with AKI requiring RRT[30]. However, they were not able to confirm this finding due to limited sample size with fluid overload. Our results revealed a U-shaped relationship between fluid balance and 28-day mortality, confirming that both positive and negative deviations from the optimal fluid balance are associated with increased risk. This view is consistent with the research conducted by Balakumar et al.[31] and Miles et al.[32]. Moreover, our study found that maintaining a 3-day cumulative fluid balance between − 2814 mL and − 445 mL was associated with improved survival. Beyond this range, reducing or stopping fluid removal should be considered. Setting de-escalation volume thresholds may help prevent hypoperfusion and hypovolemic shock, ensuring that the benefits of fluid removal consistently outweigh the risks. The optimal fluid balance range after hemodynamic stability and de-escalation targets require further investigation. Key confounders like BMI and weight change were excluded from analysis due to missing data. Volume status assessment requires integrating dynamic changes in both hemodynamic parameters and organ function including central venous pressure and serum lactate changes. Key bedside techniques include pulse pressure variation (PPV), stroke volume variation (SVV), and Venous Excess Ultrasound Score (VEXUS)[33–36]. Overall, our results provide a reference for clinical practice, this range of fluid balance should be adjusted accordingly based on specific circumstances, taking the individual baseline condition and organ function into account. Further in-depth research is needed to guide de-escalation process. In our study, there was more RRT use on day 3 and day 5 in the early group, probably indicating more RRT-based de-escalation for individuals. Our analysis revealed that early de-escalation was associated with reduced 28-day mortality across multiple subgroups, though this protective association did not reach statistical significance in the AKI subgroup. Consistent with the previous STARRT‑AKI study[37], earlier RRT initiation in critically ill patients with AKI conferred a modest decrease of cumulative fluid balance but not associated with mortality. Our results indicate that these patients may be more sensitive to the dangers of fluid overload and have a poorer tolerance to de-escalation measures. Clinical trials that evaluate optimal de-escalation strategies in patients with AKI are urgently needed. Our study has several strengths. Although there have been studies focusing on the de-escalation effect, no research has concluded when to start and to stop the de-escalation process[18]. We have large sample size with approximately 3,800 participants after PSM. It enabled us to control for confounders, thereby obtaining more accurate statistical results and providing possibility for external validation. Finally, we determined a 24-hour time point after hemodynamic stability for clinicians to make decisions. We also provided them with an accurate fluid balance range (-2814 mL to -445 mL) as a reference for further decisions on fluid de-escalation. All the suggestions are highly feasible in practice. There are still several limitations in our study. First, the observational design could not explain the causal relationship between early de-escalation and outcomes. Second, as it was a retrospective study, the level of evidence needs to be improved by RCT and other prospective studies. Moreover, MIMIC-IV is based on data from the United States, so further external validation is necessary. Finally, we included a specific subset of critically ill patients with septic shock as well as fluid balance over 2000 ml, which can introduce selection bias, making our results not generalizable to other critically ill populations. Conclusions In patients with septic shock and fluid overload, active de-escalation within 24 hours after hemodynamic stability was associated with decreased 28-day mortality, more weaning from MV, lower incidence of AKI and less hemodynamic deterioration on day 3 after hemodynamic stability. We recommend that clinicians formulate de-escalation strategy according to fluid balance. Maintaining daily fluid balance within 3 days between − 2814mL and − 445mL can be appropriate. Further prospective trials are needed to determine how de-escalation will affect clinical outcomes. Abbreviations EGDT, Early goal-directed therapy MIMIC-IV, Medical Information Mart for Intensive Care IV database SQL, Structured Query Language RECORD, Reporting of Studies Conducted Using Observational Routinely Collected Health Data reporting ICU, Intensive care unit Sepsis-3, The Third International Consensus Definitions for Sepsis and Septic Shock Lac, Lactate MAP, Mean arterial pressure RRT, Renal replacement therapy MV, Mechanical ventilation IQR, Interquartile range CCI, Charlson comorbidity index SOFA, Sequential Organ Failure Assessment AKI, Acute kidney injury PSM, Propensity score matching RCS, Restricted cubic splines POINCARE, Effects of Fluid Balance Control in Critically Ill Patients MAKE, major adverse kidney events VEXUS Score, Venous Excess Ultrasound Score SDF, Sidestream dark field CRT, Capillary refill time PPV, Pulse pressure variation SVV, Stroke volume variation STARRT‑AKI, Standard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury ER, Emergency Room HR, Hazard ratio Declarations Ethics approval and consent to participate As data have been de-identified in the MIMIC-IV database, the ethical approval statement was waived. Consent for publication Not applicable Availability of data and materials The datasets supporting the findings of this study are available in additional information and from the corresponding author on reasonable request. Competing of interests The authors have no conflicts of interest to declare relevant to this publication. Funding National Natural Science Foundation of China (82502633), National Natural Science Foundation of China (82402510), Science and Technology Commission of Shanghai Municipality (24ZR1447700), Shanghai Municipal Health Commission’s Seed Program for Medical New Technology Research and Translation (2024ZZ2045). Authors’ contributions R.Z. and R.T. designed the study, conducted the analyses, and wrote the manuscript. T.W. extracted the data. R.Z., R.T. and T.W. contributed to the data analyses and charting. Ruoming T., D.D. and Y.W. contributed to the design of the work. 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12:39:53","extension":"xml","order_by":27,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":124529,"visible":true,"origin":"","legend":"","description":"","filename":"e3553762af354ec68070844ed34d004c1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8247207/v1/0aac13fbefc2f083e2959a5a.xml"},{"id":97980434,"identity":"3a32b595-b4f3-48f8-873b-4c1cfb8b607a","added_by":"auto","created_at":"2025-12-11 12:39:52","extension":"html","order_by":28,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":134477,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8247207/v1/07094be1a7987c9c0a1eaffb.html"},{"id":97980414,"identity":"9de23d69-1fb8-4e3e-b063-93dff7e9dd4a","added_by":"auto","created_at":"2025-12-11 12:39:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1256762,"visible":true,"origin":"","legend":"\u003cp\u003ePatient flow chart. CKD chronic kidney disease, RRT renal replacement therapy, SAH subarachnoid hemorrhage, DKA diabetic ketoacidosis, MAP mean artery pressure, NE norepinephrine, CRRT continuous renal replacement therapy, PSM, propensity score matching.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8247207/v1/c2b9653adfd1df967b0d7e12.png"},{"id":97980415,"identity":"981e2029-60f2-46fe-b2b9-b3955fd619f3","added_by":"auto","created_at":"2025-12-11 12:39:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1030740,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve for 28-day all-cause mortality of patients de-escalated within or after 24h.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8247207/v1/6b6fa662130e00970dec38fd.png"},{"id":97980420,"identity":"95e05377-67bf-4bb7-9d66-9ad85d929336","added_by":"auto","created_at":"2025-12-11 12:39:51","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":709220,"visible":true,"origin":"","legend":"\u003cp\u003eRestricted cubic spline of the association between fluid balance within 3 days after hemodynamic stability and 28-day all-cause mortality in the cohort with propensity score matching. A) The association with daily fluid balance within 3 days after hemodynamic stability and 28-day all-cause mortality was expressed relative to HR and 95% confidence intervals. B) The association with accumulated fluid balance within 3 days after hemodynamic stability and 28-day all-cause mortality was expressed relative to HR and 95% confidence intervals.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8247207/v1/7818e755839f39fd363709ac.png"},{"id":98423652,"identity":"a3bad55f-c84a-4af1-9d56-86defe7154a6","added_by":"auto","created_at":"2025-12-17 16:32:28","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":6370577,"visible":true,"origin":"","legend":"\u003cp\u003eFluid balance within 3 days after hemodynamic stability for survivors or non-survivors up to 28 days. A) Daily fluid balance; B) Accumulated fluid balance. * p \u0026lt; 0.05, ** p \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8247207/v1/8a73b28f8f175c5451e6eb53.png"},{"id":101690646,"identity":"2348a0be-eeb0-4830-ac7c-7cce24834a79","added_by":"auto","created_at":"2026-02-02 16:06:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":12379459,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8247207/v1/b5afa17d-2cb4-4648-bf5f-901527a6790b.pdf"},{"id":97980437,"identity":"78fbbd6d-5c7c-4589-b2df-adc32eae268d","added_by":"auto","created_at":"2025-12-11 12:39:52","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":6057871,"visible":true,"origin":"","legend":"","description":"","filename":"Additionalfile.docx","url":"https://assets-eu.researchsquare.com/files/rs-8247207/v1/0cc98540503883a79e603fa7.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association of active fluid de-escalation timing with clinical outcomes in patients with septic shock: a multicenter cohort study","fulltext":[{"header":"Background","content":"\u003cp\u003eSepsis was a systemic inflammatory response to infection and septic shock was described as sepsis complicated by either hypotension or hyperlactatemia which could be refractory to fluid resuscitation[1]. Large volumes of fluid resuscitation are recommended for patients with septic shock to improve cardiac output and limit progression to multiple organ dysfunction and death[2]. The maladaptive excess of fluid volume having adverse effects on organ function is termed \u0026ldquo;fluid accumulation syndrome\u0026rdquo;[3]. While early goal-directed therapy (EGDT) revolutionized sepsis care by emphasizing rapid crystalloid infusion to restore perfusion, mounting evidence highlights detrimental effects of excessive fluid accumulation, including tissue oedema, impaired organ function, and increased mortality[4\u0026ndash;7]. Thus, fluid management in sepsis has evolved from a one-size-fits-all aggressive resuscitation approach to a dynamic, phased strategy that balances early hemodynamic stability with prevention of fluid overload[8]. This paradigm shift underscores the critical need for active fluid de-escalation after initial resuscitation to mitigate iatrogenic harm.\u003c/p\u003e\u003cp\u003eThe conceptual ROSE model summarizes 4 dynamic fluid phases (resuscitation, optimization, stabilization and evacuation) to maximize benefits and minimize harms in fluid therapy[9]. To achieve the goals of fluid management, we must answer 4 questions (when to start or to stop fluid therapy, and when to start or to stop fluid removal)[10]. However, current studies and guidelines focus on the initial resuscitation but fail to provide more information on fluid removal[11, 12]. Therefore, it is necessary to assess the appropriate timing and extent of fluid removal.\u003c/p\u003e\u003cp\u003eThe term \u0026ldquo;de-escalation\u0026rdquo; refers to active removal of accumulated fluid in patients with fluid overload using drugs and/or ultrafiltration (UF)[13]. Randomized clinical trial showed that conservative fluid administration and active fluid removal was feasible to reduce fluid overload compared to usual care[14]. Meanwhile, negative fluid balance was furtherly reported associated with improved outcomes[5]. However, it remains unclear referring optimal strategy of active fluid de-escalation (timing, type, dose and mode of fluid removal, combination therapy, monitoring, duration, and discontinuation)[15].\u003c/p\u003e\u003cp\u003eThus, we undertook a large-scale multicenter retrospective cohort study of patients with septic shock by using data from the Medical Information Mart for Intensive Care IV database (MIMIC-IV), aiming to help us understand the indications, approaches, endpoints, and effects of de-escalation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design\u003c/h2\u003e\u003cp\u003eThis retrospective cohort study was based on MIMIC-IV database Version 2.2 (MIMIC-IV v2.2) using Structured Query Language (SQL). The study was conducted following Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines[16].\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePopulation selection\u003c/h3\u003e\n\u003cp\u003eAll patients with septic shock recognized within 24 hours on ICU admission and eligible for de-escalation were included in main analysis. Definition of sepsis was according to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)[17]. Recognition of shock included using vasopressor, or serum lactate (Lac)\u0026thinsp;\u0026ge;\u0026thinsp;2mmol/L, or mean arterial pressure (MAP)\u0026thinsp;\u0026lt;\u0026thinsp;65mmHg. Patients were eligible for de-escalation if they achieved hemodynamic stability (with a cumulative fluid balance over 2000 mL from admission, an equivalent dose of norepinephrine lower than 0.2\u0026micro;g/kg\u0026middot;min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, Lac\u0026thinsp;\u0026lt;\u0026thinsp;2mmol/L and MAP\u0026thinsp;\u0026ge;\u0026thinsp;65mmHg as well)[14]. Administration of diuretics or ultrafiltration after hemodynamic stability was defined as an act of de-escalation. Patients diagnosed with hypovolemic shock, subarachnoid hemorrhage, diabetic ketoacidosis, chronic kidney disease and pregnancy were excluded[14]. Records without necessary data were also excluded. We excluded those with ICU stays less than 24h or those with de-escalation before hemodynamic stability. Only the first ICU stay were included in analysis. Patients eligible for de-escalation yet without records of active de-escalation were analyzed prior to our main analysis. We then grouped the main analysis cohort into two groups according to hours from hemodynamic stability to the time of de-escalation, of which median value was 21.18 hours \u003cb\u003e(e-Figure 1)\u003c/b\u003e. Early de-escalation group included patients with de-escalation within 24 hours after hemodynamic stability. Late de-escalation group included the rest.\u003c/p\u003e\n\u003ch3\u003eVariables and outcomes\u003c/h3\u003e\n\u003cp\u003eDemographics, comorbidities, fluid administration, severity of illness, cumulative fluid balance, renal replacement therapy (RRT) and mechanical ventilation (MV) administration on Day 1 of hemodynamic stability were gathered. The primary outcome was 28-day all-cause mortality from hemodynamic stability. Secondary outcomes included administration of MV and RRT, kidney injury and hemodynamic deterioration on Day 3 and Day 5 after enrollment. Hemodynamic deterioration was recognized as higher equivalent dose vasopressors, or newly vasopressor administration after enrollment. Daily and accumulated fluid balance within 3 days after hemodynamic stability were also collected.\u003c/p\u003e\u003cp\u003eStudy Day 1 was a period of 24 hours after enrollment and subsequent study days were consecutive 24-hour periods. Fluid balance was the total delivered input (intravenous medications, fluid boluses, blood products, enteral and parenteral nutrition, and maintenance) minus total measured output (urine, ultrafiltrate, surgical drains) as recorded.\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eSkewed continuous variables were presented as medians with interquartile ranges (IQRs) and were compared using Wilcoxon rank-sum test. Categorial variables were presented as counts and percentages and were compared using Chi-square test or Fisher\u0026rsquo;s exact test.\u003c/p\u003e\u003cp\u003ePre-defined confounders included Charlson comorbidity index (CCI), number of infection sites, whether admitted from emergency department, age, gender, ethnicity, and colloid administration, albumin administration, Sequential Organ Failure Assessment (SOFA) score, acute kidney injury (AKI), MV use, and cumulative fluid balance till hemodynamic stability.\u003c/p\u003e\u003cp\u003eAssociation of de-escalation and 28-day mortality was analyzed using univariable and multivariable logistic regression priorly. The multivariable regression model was adjusted for the pre-defined confounders.\u003c/p\u003e\u003cp\u003eVariables with \u0026gt;\u0026thinsp;30% missing values were excluded to minimize the bias, and the other were processed using multiple imputation method. The cohort for main analysis were then furtherly processed through propensity score matching (PSM). PSM was applied with a caliper width of 0.02 to mitigate baseline imbalances and paired in a 1:1 ratio using the nearest neighbor matching technique for pre-defined confounders. The efficacy of PSM was evaluated by the standardized mean difference (SMD) with an SMD\u0026thinsp;\u0026lt;\u0026thinsp;0.1 indicating a balanced model.\u003c/p\u003e\u003cp\u003eKaplan-Meier method with log-rank test and landmark analysis were used to illustrate survival for 28 days after hemodynamic stability. Potential nonlinear association of fluid balance after hemodynamic stability with 28-day all-cause mortality was then demonstrated using restricted cubic splines (RCS) with five knots located at the 5th, 35th, 50th, 65th, and 95th percentiles based on Cox regression.\u003c/p\u003e\u003cp\u003eSubgroup analysis for primary outcome was conducted for: (1)\u0026thinsp;\u0026ge;\u0026thinsp;65-year vs. \u0026lt; 65-year ; (2) SOFA score\u0026thinsp;\u0026ge;\u0026thinsp;6 vs. \u0026lt; 6; (3) Lactate\u0026thinsp;\u0026ge;\u0026thinsp;4mmol/L vs. \u0026lt; 4mmol/L; (4) with vs. without MV on Day 1 of enrollment; (5) with vs. without heart failure; (6) with vs. without urinary infection; (7) with vs. without blood infection; (8) with vs. without abdominal infection; (9) with vs. without pneumonia.\u003c/p\u003e\u003cp\u003eStatistical analysis and plotting were constructed using R Statistical Software (v4.4.3; R Core Team 2025) and GraphPad Prism version 10.4.1 for Mac OS X (GraphPad Software, Boston, Massachusetts USA). Statistical significance was represented as \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for two-sided hypothesis.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eData access\u003c/h3\u003e\n\u003cp\u003eContemporary electronic health records and all personal information in MIMIC-IV database have been de-identified, so that patient consent and ethical approval was waived. Data extraction was conducted by the researcher (TW) through qualified access (Certificate No.33461595).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003ePatient Characteristics\u003c/h2\u003e\u003cp\u003eThis cohort study included 10,907 patients with septic shock who met the inclusion criteria, among whom 5,782 had records of de-escalation after enrollment. De-escalation after hemodynamic stability was affirmed associated with decreased 28-day mortality by logistic regression model (\u003cb\u003ee-\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Median time of 21.18 hours from hemodynamic stability to de-escalation was showed in distribution density plot \u003cb\u003e(e-Figure 1)\u003c/b\u003e. Therefore, we set 24 hours as the cut-off time for grouping to better meet clinical needs, 3,255 cases underwent de-escalation within 24 hours and 2,527 cases after 24 hours. 1,898 pairs of patients were matched after PSM (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Clinical information in both groups before and after PSM is presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Patients in late group were found with higher SOFA scores (7 [5 to 9] vs. 6 [4 to 8]), more AKI incidence (33.3% vs. 27.8%) and emergency room admission (87.3 vs. 70%) before PSM. Furthermore, patients in early group had a higher cumulative fluid balance till hemodynamic stability (2,875 [2,335 to 3,750] vs. 2,573 [2,223 to 3,500]) and received more colloids (67% vs. 49%). Nevertheless, no statistically significant differences were observed between two groups in CCI (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.924) or age (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.915). The imbalance was minimized after PSM.\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\u003eBaseline characteristics of the patients before and after PSM.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\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\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003eBefore PSM\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e\u003cp\u003eAfter PSM\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOverall\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;5782)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDe-escalation after 24h\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;2527)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDe-escalation within 24h\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;3255)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOverall\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;3796)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eDe-escalation after 24h\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;1898)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDe-escalation within 24h\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;1898)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e\u003cp\u003eDemographic\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, yrs, median [IQR]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e68 [59, 78]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e67 [56, 78]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e69 [60, 78]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e68 [58, 78]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e68 [57, 79]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e68 [59, 77]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.915\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender, n (%)\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\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.895\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2268 (39.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1090 (43.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1178 (36.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1533 (40.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e764 (40.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e769 (40.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3514 (60.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1437 (56.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2077 (63.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2263 (59.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1134 (59.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1129 (59.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEthnicity, n (%)\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\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.329\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWhite\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4017 (69.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1666 (65.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2351 (72.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2584 (68.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1288 (67.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1296 (68.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlack\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e336 (5.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e179 (7.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e157 (4.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e230 (6.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e125 (6.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e105 (5.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAsian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e143 (2.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e63 (2.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e80 (2.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e91 (2.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e42 (2.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e49 (2.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLatino\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e156 (2.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e66 (2.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e90 (2.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e103 (2.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e44 (2.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e59 (3.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1130 (19.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e553 (21.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e577 (17.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e788 (20.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e399 (21.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e389 (20.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdmitted to ER, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4484 (77.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2206 (87.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2278 (70.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3219 (84.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1601 (84.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1618 (85.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.470\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eComorbidities\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCCI, median [IQR]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 [3, 6]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 [3, 7]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 [3, 6]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.924\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5 [3, 7]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e5 [3, 7]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e5.00 [3, 7]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.534\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMyocardial infarct, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1231 (21.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e440 (17.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e791 (24.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e850 (22.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e355 (18.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e495 (26.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCongestive heart failure, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1719 (29.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e660 (26.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1059 (32.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1185 (31.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e513 (27.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e672 (35.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeripheral vascular disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e900 (15.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e339 (13.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e561 (17.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e594 (15.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e274 (14.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e320 (16.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.044\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCerebrovascular disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e715 (12.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e368 (14.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e347 (10.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e491 (12.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e276 (14.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e215 (11.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDementia, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e135 (2.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e88 (3.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e47 (1.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e92 (2.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e57 (3.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e35 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.027\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic pulmonary disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1532 (26.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e675 (26.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e857 (26.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.766\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1039 (27.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e512 (27.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e527 (27.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.610\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRheumatic disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e218 (3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e104 (4.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e114 (3.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.252\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e145 (3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e76 (4.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e69 (3.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.611\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeptic ulcer disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e139 (2.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e89 (3.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e50 (1.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e102 (2.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e62 (3.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e40 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.035\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiver disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1066 (18.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e599 (23.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e467 (14.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e486 (12.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e279 (14.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e207 (10.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1810 (31.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e687 (27.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1123 (34.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1163 (30.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e516 (27.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e647 (34.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParaplegia, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e198 (3.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e127 (5.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e71 (2.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e143 (3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e89 (4.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e54 (2.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMalignant cancer, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e524 (9.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e295 (11.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e229 (7.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e376 (9.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e212 (11.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e164 (8.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSevere liver disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e259 (4.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e165 (6.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e94 (2.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e193 (5.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e120 (6.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e73 (3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetastatic solid tumor, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e201 (3.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e136 (5.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e65 (2.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e154 (4.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e101 (5.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e53 (2.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSource of infection\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUpper respiratory infection, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e439 (7.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e274 (10.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e165 (5.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e297 (7.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e144 (7.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e153 (8.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.629\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePneumonia, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e802 (13.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e506 (20.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e296 (9.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e572 (15.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e297 (15.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e275 (14.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.341\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbdominal infection, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e326 (5.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e220 (8.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e106 (3.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e217 (5.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e116 (6.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e101 (5.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.328\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrinary infection, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e777 (13.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e437 (17.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e340 (10.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e551 (14.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e244 (12.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e307 (16.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood infection, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1251 (21.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e830 (32.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e421 (12.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e891 (23.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e489 (25.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e402 (21.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSoft tissue infection, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45 (0.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38 (1.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 (0.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e41 (1.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e23 (1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e18 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.530\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCNS infection, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e279 (4.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e175 (6.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e104 (3.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e31 (0.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e24 (1.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e7 (0.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther infection, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45 (0.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38 (1.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 (0.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e185 (4.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e87 (4.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e98 (5.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.451\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of infection sites, n (%)\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\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.018\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo specific site\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3320 (57.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1012 (40.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2308 (70.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1985 (52.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e950 (50.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1035 (54.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1345 (23.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e789 (31.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e556 (17.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1062 (28.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e579 (30.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e483 (25.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e794 (13.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e503 (19.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e291 (8.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e562 (14.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e281 (14.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e281 (14.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e248 (4.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e166 (6.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e82 (2.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e152 (4.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e70 (3.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e82 (4.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e68 (1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15 (0.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e32 (0.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e17 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e15 (0.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (0.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (0.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (0.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3 (0.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1 (0.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e2 (0.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCharacteristics on Day 1 of hemodynamic stability\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSOFA score on Day 1 of hemodynamic stability median [IQR]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 [5, 9]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 [5, 9]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 [4, 8]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6 [5, 9]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e7 [5, 9]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e6 [5, 9]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.337\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVentilation on Day 1 of hemodynamic stability, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4668 (80.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2080 (82.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2588 (79.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3068 (80.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1546 (81.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1522 (80.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.343\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAKI on Day 1 of hemodynamic stability, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1747 (30.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e841 (33.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e906 (27.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1254 (33.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e628 (33.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e626 (33.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.973\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAccumulated fluid balance on Day 1 of hemodynamic stability, mL, median [IQR]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2726 [2285, 3700]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2573 [2223, 3500]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2875 [2335, 3750]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2630 [2253, 3555]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2597 [2239, 3500]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e2676 [2273, 3600]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.030\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCategories of fluid administered before hemodynamic stability\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCrystalloid, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5619 (97.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2448 (96.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3171 (97.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.245\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3672 (96.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1840 (96.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1832 (96.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.523\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eColloid, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3417 (59.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1237 (49.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2180 (67.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2031 (53.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1028 (54.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1003 (52.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.435\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNutrient, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e435 (7.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e196 (7.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e239 (7.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.588\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e308 (8.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e148 (7.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e160 (8.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.513\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlbumin, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e615 (10.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e280 (11.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e335 (10.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.357\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e408 (10.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e197 (10.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e211 (11.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.496\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003ePSM: Propensity Score Matching; ER: Emergency Room; CCI: Charlson Comorbidity Index; CNS: Central Nervous System; SOFA: Sequential Organ Failure Assessment; AKI: Acute Kidney Injury; IQR: Interquartile Range.\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\n\u003ch3\u003ePrimary outcome\u003c/h3\u003e\n\u003cp\u003eThe 28-day mortality for patients from early de-escalation group was lower than that observed in late group (12.6% vs. 18.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The Kaplan\u0026ndash;Meier survival analysis for 28-day survival is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. In 7-day landmark analysis of matched population, the survival rate of early group was similar to that of late group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.428); however, the 28-day mortality of early group was lower than that in late group (log-rank \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\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=\"5\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOutcomes\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOverall\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;3796)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDe-escalation after 24h\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;1898)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDe-escalation within 24h\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;1898)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003ePrimary outcome\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e28-day all-cause mortality, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e580 (15.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e341 (18.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e239 (12.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSecondary outcome\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMV administration and weaning\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of MV, hours, median [IQR]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24.50 [10.70, 117.00]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e60.50 [14.85, 170.00]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17.00 [8.91, 61.47]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of MV after hemodynamic stability, hours, median [IQR]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.66 [0.00, 67.60]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17.20 [0.00, 111.25]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.59 [0.00, 25.70]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUse of MV on Day 3 after hemodynamic stability, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1455 (38.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e980 (51.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e475 (25.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeterioration of patients with MV on Day 3 after hemodynamic stability, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e70 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50 (2.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20 (1.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWeaning from MV on Day 3 after hemodynamic stability, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1683 (44.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e616 (32.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1067 (56.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUse of MV on Day 5 after hemodynamic stability, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e483 (12.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e303 (16.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e180 (9.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeterioration of patients with MV on Day 5 after hemodynamic stability, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 (0.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 (0.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.045\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWeaning from MV on Day 5 after hemodynamic, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2610 (68.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1261 (66.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1349 (71.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRRT administration and AKI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUse of RRT on Day 3 after hemodynamic stability, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e149 (3.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e62 (3.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e87 (4.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.045\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKidney injury on Day 3 after hemodynamic stability, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e602 (15.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e324 (17.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e278 (14.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.046\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUse of RRT on Day 5 after hemodynamic stability, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e120 (3.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e48 (2.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e72 (3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.033\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKidney injury on Day 5 after hemodynamic stability, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e431 (11.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e220 (11.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e211 (11.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.682\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eShock\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHemodynamic deterioration on Day 3 after hemodynamic stability, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e520 (13.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e304 (16.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e216 (11.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHemodynamic deterioration on Day 5 after hemodynamic stability, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e534 (14.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e311 (16.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e223 (11.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eRRT: Renal Replacement Therapy; MV: Mechanical Ventilation; AKI: Acute Kidney Injury; SOFA: Sequential Organ Failure Assessment; IQR: Interquartile Range.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSecondary outcomes\u003c/h2\u003e\u003cp\u003eThere were differences between early de-escalation group and late group with statistical significance in terms of MV and RRT administration, kidney injury and hemodynamic deterioration in the matched cohort (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Patients in early group had a shorter duration of MV during ICU stay (17.00 [8.91 to 61.47] vs.60.50 [14.85 to 170.00], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and after hemodynamic stability (5.59 [0.00 to 25.70] vs. 17.20 [0.00 to 111.25], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003eOn day 3, we found less use of MV (25% vs. 51.6%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), less deterioration among the patients who received MV (1.1 vs.2.6%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and more weaning from MV (56.2% vs.32.5%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in early de-escalation group. Meanwhile, lower incidence of AKI (14.6% vs.17.1%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.046) and less hemodynamic deterioration (11.4% vs. 16%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were observed in early group on day 3. On day 5, similar outcomes were also observed in both MV administration and hemodynamic deterioration, while there was no statistically significant difference in terms of kidney injury.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eFluid balance and clinical outcomes\u003c/h2\u003e\u003cp\u003eFluid balance over time is shown in e-\u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e. Patients in early group had a lower daily fluid balance than those in late group within 3 days after hemodynamic stability (\u0026minus;\u0026thinsp;770 [\u0026minus;\u0026thinsp;1604 to 2] vs. \u0026minus;29 [\u0026minus;\u0026thinsp;842 to 993], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Cumulative fluid balance was lower in early group on day 2 and day 3. Lower fluid balance was observed in survivors than in non-survivors (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). To more clearly elucidate the relationship between fluid balance and the risk of 28-day all-cause mortality, we performed RCS analysis on the total population (\u003cb\u003ee-Figure 2\u003c/b\u003e) and the population after PSM (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). RCS model revealed a U-shaped connection between fluid balance within 3 days after hemodynamic stability and 28-day all-cause mortality (\u003cem\u003eP\u003c/em\u003e for non-linear\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Daily fluid balance of \u0026minus;\u0026thinsp;1482mL and accumulated fluid balance within 3 days of \u0026minus;\u0026thinsp;4446mL are associated with the lowest HR for 28-day all-cause mortality, respectively. Daily fluid balance between \u0026minus;\u0026thinsp;2814mL and \u0026minus;\u0026thinsp;445mL and accumulated fluid balance within 3 days between \u0026minus;\u0026thinsp;8443mL and \u0026minus;\u0026thinsp;1337mL were associated with HR for 28-day all-cause mortality lower than 1, respectively.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eSubgroup analyses\u003c/h2\u003e\u003cp\u003eConsistent association between early active de-escalation and lower 28-day all-cause mortality in patients with septic shock was found through subgroup analyses. For patients with lac\u0026thinsp;\u0026ge;\u0026thinsp;4 mmol/L, AKI, blood infection, abdominal infection and pneumonia, this correlation was not statistically significant (\u003cb\u003ee-Figure 3\u003c/b\u003e).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eEarlier resuscitation is core to maintaining primary hemodynamic stability, restoring tissue perfusion and oxygenation associated with reduced mortality in patients with sepsis[18, 19]. However, large fluid volume results in severe tissue oedema and increased interstitial fluid in vital organs leading to endothelial injury and impaired oxygen and metabolite diffusion[20]. Moreover, observational studies demonstrate the association between fluid overload and adverse outcomes such as higher mortality and prolonged MV support in critical illness states[4, 5, 21, 22]. Despite growing evidence opposing excessively positive fluid balance, fluid overload remains common in ICU patients.\u003c/p\u003e\u003cp\u003eTwo complementary strategies have evolved to address the issue of fluid overload: restrictive fluid administration or active fluid de-resuscitation (de-escalation)[5]. A restrictive fluid resuscitation approach has been investigated while several randomized trials observed no significant benefits for patients with septic shock[23, 24]. POINCARE-2 conservative strategy did not reduce 60-day mortality in a recent stepped wedge cluster open‑label randomized controlled trial. Actual exposure to fluid removal strategy might not be reflected and further analyses required[25]. Another approach is de-escalation therapy, which actively removes excess fluid through diuretics and/or ultrafiltration[13]. Negative fluid balance achieved by active de-escalation was reported associated with improved outcomes[5]. Similarly, we found that de-escalation within 24 hours after hemodynamic stability yielded better results in terms of 28-day mortality, MV administration, AKI incidence and hemodynamic changes. Another study also found latent decreasing fluid balance trajectory in patients associated with a decreased risk of hospital mortality and major adverse kidney events (MAKE) in critically ill patients with septic shock[26]. Thus, de-escalation can directly affect the fluid balance trajectory in patients with fluid overload. However, current studies and guidelines cannot answer when to start or to stop fluid removal[2, 27].\u003c/p\u003e\u003cp\u003eTo answer the question about when to start de-escalation, we conducted the following research. We selected patients with septic shock and fluid balance over 2000 ml with an equivalent dose of norepinephrine lower than 0.2\u0026micro;g/kg\u0026middot;min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e to start de-escalation according to the RADAR-2 study[14]. Interestingly, we found that the median de-escalation time for these patients was 21.18 hours, yet distribution of the cohort was obviously biased when grouped by other timepoints such as 6 hours, 12 hours. Therefore, we set 24 hours after hemodynamic stability as a critical timepoint, which is helpful for clinicians to make decisions. Furtherly, clinicians should consider multiple factors when assessing fluid overload and hemodynamic stability. This requires prospective clinical data (e.g., imaging studies) as well as dynamic monitoring of brain natriuretic peptide and urine output changes. Although the 24-hour grouping predicted outcomes differently, this specific timepoint was chosen artificially and might not be the best marker for deciding when to de-escalate treatment. Future studies should use personalized data to develop models that predict the best timing. Additionally, since responses to diuretics and RRT vary greatly among individuals, more research is needed to optimize de-escalation strategies[28, 29].\u003c/p\u003e\u003cp\u003eTo answer the question about when to stop fluid de-escalation, we need to find the association between volume of de-escalation and clinical outcomes. Woodward et al. used cubic spline to find a potentially U-shaped nonlinear relation between fluid overload and MAKE in critically ill patients with AKI requiring RRT[30]. However, they were not able to confirm this finding due to limited sample size with fluid overload. Our results revealed a U-shaped relationship between fluid balance and 28-day mortality, confirming that both positive and negative deviations from the optimal fluid balance are associated with increased risk. This view is consistent with the research conducted by Balakumar et al.[31] and Miles et al.[32]. Moreover, our study found that maintaining a 3-day cumulative fluid balance between \u0026minus;\u0026thinsp;2814 mL and \u0026minus;\u0026thinsp;445 mL was associated with improved survival. Beyond this range, reducing or stopping fluid removal should be considered. Setting de-escalation volume thresholds may help prevent hypoperfusion and hypovolemic shock, ensuring that the benefits of fluid removal consistently outweigh the risks. The optimal fluid balance range after hemodynamic stability and de-escalation targets require further investigation. Key confounders like BMI and weight change were excluded from analysis due to missing data. Volume status assessment requires integrating dynamic changes in both hemodynamic parameters and organ function including central venous pressure and serum lactate changes. Key bedside techniques include pulse pressure variation (PPV), stroke volume variation (SVV), and Venous Excess Ultrasound Score (VEXUS)[33\u0026ndash;36]. Overall, our results provide a reference for clinical practice, this range of fluid balance should be adjusted accordingly based on specific circumstances, taking the individual baseline condition and organ function into account. Further in-depth research is needed to guide de-escalation process.\u003c/p\u003e\u003cp\u003eIn our study, there was more RRT use on day 3 and day 5 in the early group, probably indicating more RRT-based de-escalation for individuals. Our analysis revealed that early de-escalation was associated with reduced 28-day mortality across multiple subgroups, though this protective association did not reach statistical significance in the AKI subgroup. Consistent with the previous STARRT‑AKI study[37], earlier RRT initiation in critically ill patients with AKI conferred a modest decrease of cumulative fluid balance but not associated with mortality. Our results indicate that these patients may be more sensitive to the dangers of fluid overload and have a poorer tolerance to de-escalation measures. Clinical trials that evaluate optimal de-escalation strategies in patients with AKI are urgently needed.\u003c/p\u003e\u003cp\u003eOur study has several strengths. Although there have been studies focusing on the de-escalation effect, no research has concluded when to start and to stop the de-escalation process[18]. We have large sample size with approximately 3,800 participants after PSM. It enabled us to control for confounders, thereby obtaining more accurate statistical results and providing possibility for external validation. Finally, we determined a 24-hour time point after hemodynamic stability for clinicians to make decisions. We also provided them with an accurate fluid balance range (-2814 mL to -445 mL) as a reference for further decisions on fluid de-escalation. All the suggestions are highly feasible in practice.\u003c/p\u003e\u003cp\u003eThere are still several limitations in our study. First, the observational design could not explain the causal relationship between early de-escalation and outcomes. Second, as it was a retrospective study, the level of evidence needs to be improved by RCT and other prospective studies. Moreover, MIMIC-IV is based on data from the United States, so further external validation is necessary. Finally, we included a specific subset of critically ill patients with septic shock as well as fluid balance over 2000 ml, which can introduce selection bias, making our results not generalizable to other critically ill populations.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn patients with septic shock and fluid overload, active de-escalation within 24 hours after hemodynamic stability was associated with decreased 28-day mortality, more weaning from MV, lower incidence of AKI and less hemodynamic deterioration on day 3 after hemodynamic stability. We recommend that clinicians formulate de-escalation strategy according to fluid balance. Maintaining daily fluid balance within 3 days between \u0026minus;\u0026thinsp;2814mL and \u0026minus;\u0026thinsp;445mL can be appropriate. Further prospective trials are needed to determine how de-escalation will affect clinical outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eEGDT, Early goal-directed therapy\u003c/p\u003e\n\u003cp\u003eMIMIC-IV, Medical Information Mart for Intensive Care IV database\u003c/p\u003e\n\u003cp\u003eSQL, Structured Query Language\u003c/p\u003e\n\u003cp\u003eRECORD, Reporting of Studies Conducted Using Observational Routinely Collected Health Data reporting\u003c/p\u003e\n\u003cp\u003eICU, Intensive care unit\u003c/p\u003e\n\u003cp\u003eSepsis-3, The Third International Consensus Definitions for Sepsis and Septic Shock\u003c/p\u003e\n\u003cp\u003eLac, Lactate\u003c/p\u003e\n\u003cp\u003eMAP, Mean arterial pressure\u003c/p\u003e\n\u003cp\u003eRRT, Renal replacement therapy\u003c/p\u003e\n\u003cp\u003eMV, Mechanical ventilation\u003c/p\u003e\n\u003cp\u003eIQR, Interquartile range\u003c/p\u003e\n\u003cp\u003eCCI, Charlson comorbidity index\u003c/p\u003e\n\u003cp\u003eSOFA, Sequential Organ Failure Assessment\u003c/p\u003e\n\u003cp\u003eAKI, Acute kidney injury\u003c/p\u003e\n\u003cp\u003ePSM, Propensity score matching\u003c/p\u003e\n\u003cp\u003eRCS, Restricted cubic splines\u003c/p\u003e\n\u003cp\u003ePOINCARE, Effects of Fluid Balance Control in Critically Ill Patients\u003c/p\u003e\n\u003cp\u003eMAKE, major adverse kidney events\u003c/p\u003e\n\u003cp\u003eVEXUS Score, Venous Excess Ultrasound Score\u003c/p\u003e\n\u003cp\u003eSDF, Sidestream dark field\u003c/p\u003e\n\u003cp\u003eCRT, Capillary refill time\u003c/p\u003e\n\u003cp\u003ePPV, Pulse pressure variation\u003c/p\u003e\n\u003cp\u003eSVV, Stroke volume variation\u003c/p\u003e\n\u003cp\u003eSTARRT‑AKI, Standard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury\u003c/p\u003e\n\u003cp\u003eER, Emergency Room\u003c/p\u003e\n\u003cp\u003eHR, Hazard ratio\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs data have been de-identified in the MIMIC-IV database, the ethical approval statement was waived.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets supporting the findings of this study are available in additional information and from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare relevant to this publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNational Natural Science Foundation of China (82502633), National Natural Science Foundation of China (82402510), Science and Technology Commission of Shanghai Municipality (24ZR1447700), Shanghai Municipal Health Commission\u0026rsquo;s Seed Program for Medical New Technology Research and Translation (2024ZZ2045).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eR.Z. and R.T. designed the study, conducted the analyses, and wrote the manuscript. T.W. extracted the data. R.Z., R.T. and T.W. contributed to the data analyses and charting. Ruoming T., D.D. and Y.W. contributed to the design of the work. X.W., H.Q. and T.W. assisted and supervised the conduction of the study and edited the manuscript. All the authors approved the final version of this manuscript and agreed to take responsibilities for the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial/Nonfinancial Disclosures:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBone RC, Sibbald WJ, Sprung CL: \u003cstrong\u003eThe ACCP-SCCM consensus conference on sepsis and organ failure\u003c/strong\u003e. \u003cem\u003eChest \u003c/em\u003e1992, \u003cstrong\u003e101\u003c/strong\u003e(6):1481-1483.\u003c/li\u003e\n\u003cli\u003eEvans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, McIntyre L, Ostermann M, Prescott HC\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eSurviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021\u003c/strong\u003e. 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Pereira AJ, Timenetsky KT, Silva J\u0026uacute;nior JM, Takaoka F, de Backer D\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAssessment of fluid responsiveness using pulse pressure variation, stroke volume variation, plethysmographic variability index, central venous pressure, and inferior vena cava variation in patients undergoing mechanical ventilation: a systematic review and meta-analysis\u003c/strong\u003e. \u003cem\u003eCrit Care \u003c/em\u003e2024, \u003cstrong\u003e28\u003c/strong\u003e(1):289.\u003c/li\u003e\n\u003cli\u003eWald R, Kirkham B, daCosta BR, Ghamarian E, Adhikari NKJ, Beaubien-Souligny W, Bellomo R, Gallagher MP, Goldstein S, Hoste EAJ\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eFluid balance and renal replacement therapy initiation strategy: a secondary analysis of the STARRT-AKI trial\u003c/strong\u003e. \u003cem\u003eCrit Care \u003c/em\u003e2022, \u003cstrong\u003e26\u003c/strong\u003e(1):360.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"De-escalation, Septic shock, Fluid therapy, Timing, Clinical outcomes","lastPublishedDoi":"10.21203/rs.3.rs-8247207/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8247207/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eEarly fluid resuscitation is a basic therapy for patients with septic shock but may lead to fluid overload associated with poor clinical outcomes. Active de-escalation (accumulated fluid removal using diuretics or ultrafiltration) is a crucial part of fluid management.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eIn this retrospective cohort study, patients were classified as the early group (with septic shock receiving active de-escalation within 24 hours after hemodynamic stability) and late group. The primary outcome was 28-day mortality. Secondary outcomes included use of mechanical ventilation and renal replacement therapy, incidence of kidney injury and hemodynamic deterioration. Landmark analysis and restricted cubic splines based on Cox regression were performed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 5,782 patients were included, with 3,255 cases underwent de-escalation within 24 hours after hemodynamic stability and 1,898 pairs of patients were matched after propensity score matching. Patients in the early group were found with lower 28-day mortality (12.6% vs. 18.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), more weaning from mechanical ventilation (32.5% vs. 56.2%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), lower incidence of AKI (14.6% vs.17.1%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.046) and hemodynamic deterioration (11.4 vs. 16%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) on day 3. Similar outcomes were observed on day 5. A U-shaped association between fluid balance and 28-day mortality was observed. Daily fluid balance of \u0026minus;\u0026thinsp;1482mL within 3 days is associated with the lowest HR for 28-day mortality and range from \u0026minus;\u0026thinsp;2814mL to \u0026minus;\u0026thinsp;445mL represents HR lower than 1 for 28-day mortality.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eEarly de-escalation was associated with improved prognosis for patients with septic shock and fluid overload. Maintaining fluid balance in an optimal range could be beneficial and a de-escalation strategy according to fluid balance is recommended.\u003c/p\u003e\u003ch2\u003eClinical Trial Number:\u003c/h2\u003e\u003cp\u003eNot applicable\u003c/p\u003e","manuscriptTitle":"Association of active fluid de-escalation timing with clinical outcomes in patients with septic shock: a multicenter cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-11 12:39:46","doi":"10.21203/rs.3.rs-8247207/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-22T06:31:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-19T08:18:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-10T05:49:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"77949769904657523059578692209597736885","date":"2025-12-09T07:52:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"59634355523998088921979651786011115594","date":"2025-12-09T02:16:02+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-08T10:55:47+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-04T04:29:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-02T01:33:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-02T01:32:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-12-01T07:13:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"27650802-219d-43f5-b253-6c56fdeac12c","owner":[],"postedDate":"December 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-02T16:02:48+00:00","versionOfRecord":{"articleIdentity":"rs-8247207","link":"https://doi.org/10.1186/s12879-026-12554-w","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2026-01-27 15:58:57","publishedOnDateReadable":"January 27th, 2026"},"versionCreatedAt":"2025-12-11 12:39:46","video":"","vorDoi":"10.1186/s12879-026-12554-w","vorDoiUrl":"https://doi.org/10.1186/s12879-026-12554-w","workflowStages":[]},"version":"v1","identity":"rs-8247207","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8247207","identity":"rs-8247207","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}