Combination Therapy of Albumin and Loop Diuretics May Improve Survival in Patients with Sepsis Receiving Mechanical Ventilation: A Propensity Score Matched Analysis

Combination Therapy of Albumin and Loop Diuretics May Improve Survival in Patients with Sepsis Receiving Mechanical Ventilation: A Propensity Score Matched Analysis | 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 Combination Therapy of Albumin and Loop Diuretics May Improve Survival in Patients with Sepsis Receiving Mechanical Ventilation: A Propensity Score Matched Analysis Xisi He, Shuiqing Gui, Zhiye Zou This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8607908/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background: Fluid overload and hypoalbuminemia are typical and associated with poor outcomes in patients with sepsis receiving mechanical ventilation. While loop diuretics are used for fluid management, their efficacy can be limited by intravascular volume depletion and hypoalbuminemia. This study examines whether the combined administration of albumin and loop diuretics enhances clinical outcomes in this high-risk population. Methods: In this retrospective cohort study utilizing the MIMIC-IV database, adult patients with sepsis who required mechanical ventilation were categorized into two groups: those receiving albumin alone and those receiving albumin in combination with loop diuretics. Propensity score matching was employed to ensure balance in baseline characteristics between the groups. The primary outcome of the study was in-hospital mortality, while secondary outcomes included mortality rates at 30 and 90 days, length of hospital stay, and fluid balance. Results: After matching, a total of 1,032 patients were included in each group. The in-hospital mortality rate was significantly lower in the combination therapy group compared to the albumin-alone group (21.2% vs. 33.0%, p < 0.001). Similarly, the 30-day (22.4% vs. 32.8%) and 90-day (28.3% vs. 40.0%) mortality rates were also reduced, with both differences being statistically significant (p < 0.001). The combination therapy group exhibited a significantly lower 7-day fluid balance (1,462 mL vs. 4,304 mL, p < 0.001), despite longer durations of ICU and hospital stays. Subgroup analyses indicated a consistent benefit across most subgroups. A dose-response relationship was observed, with low-to-moderate furosemide-equivalent doses (80 mg/day) did not demonstrate any survival advantage. Conclusion: In patients with sepsis receiving mechanical ventilation, the combination of albumin and loop diuretics may be associated with reduced 30-day and 90-day mortality, as well as improved fluid balance compared to the use of albumin alone. The benefits appear to be dose-dependent, favoring low to moderate diuretic intensity. These findings suggest a potential therapeutic role for the combined use of albumin and loop diuretic therapy in this patient population. Sepsis Mechanical ventilation Albumin Loop diuretics Propensity score matching Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Sepsis remains a leading cause of morbidity and mortality in intensive care units (ICUs), frequently complicated by acute respiratory failure that necessitates invasive mechanical ventilation (MV) [ 1 , 2 ]. Managing fluid balance in this critically ill population presents a persistent challenge. While early fluid resuscitation is fundamental in septic shock [ 3 , 4 ], accumulating evidence suggests that a positive cumulative fluid balance following initial stabilization is associated with prolonged mechanical ventilation, extended ICU stays, and increased mortality [ 5 – 7 ]. In this context, strategies to facilitate fluid mobilization during the post-resuscitation phase are of substantial clinical interest. Loop diuretics are commonly employed to promote diuresis; however, their efficacy may be limited in critically ill patients due to factors such as impaired renal perfusion and altered pharmacokinetics [ 8 , 9 ]. Concurrent hypoalbuminemia, often observed in severe sepsis, can further attenuate the diuretic response by reducing intravascular oncotic pressure and decreasing the renal delivery of protein-bound loop diuretics [ 10 , 11 ].The concomitant administration of albumin with loop diuretics has been proposed as a strategy to potentially enhance diuretic efficacy. Theoretically, albumin infusion may improve intravascular volume status and renal perfusion, thereby increasing the delivery of diuretics to their site of action in the nephron [ 12 , 13 ]. Although this combined approach is sometimes utilized in clinical practice, its impact on meaningful clinical outcomes, particularly survival in mechanically ventilated septic patients, is not well established. Robust evidence from large-scale studies is lacking. Consequently, we conducted a retrospective cohort study utilizing data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Our primary objective was to investigate whether the combination of albumin and loop diuretics, as opposed to albumin alone, is associated with a reduction in in-hospital mortality among adult septic patients requiring mechanical ventilation. Secondary objectives included evaluating the effects on 30- and 90-day mortality, length of stay, fluid balance, and exploring potential dose-response relationships. Methods Data source and study design This retrospective cohort study utilized data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, version 2.0 (available at https://physionet.org/content/mimiciv/2.0/ ). The database contains de-identified clinical information from 76,943 ICU admissions at Beth Israel Deaconess Medical Center (BIDMC) between 2008 and 2019. Access to the database was authorized after completion of the Collaborative Institutional Training Initiative (CITI) program (certification number for author ZYZ: 59729494). The study protocol was approved by the Research Ethics Committee of Shenzhen Second People’s Hospital. All data were handled in compliance with HIPAA regulations, and the study adhered to the STROBE guidelines for observational research. Study population Adult patients (aged ≥ 18 years) with sepsis requiring invasive mechanical ventilation were included. Sepsis was defined according to the Sepsis-3 criteria, based on a Sequential Organ Failure Assessment (SOFA) score increase of 2 points or more with suspected or confirmed infection [ 14 ]. Patients were excluded if they were younger than 18 years or older than 90 years, stayed in the ICU for less than 24 hours or more than 100 days, died within the first 24 hours of ICU admission, had sepsis onset before ICU admission (12 hours) or after ICU admission (24 hours), or had received albumin or loop diuretics before ICU admission. For patients with multiple ICU admissions during the same hospitalization, only data from the first ICU admission were included. Exposure and comparator Patients were classified into two groups based on the treatment they received during their stay in the ICU. Albumin-alone group: Received albumin (5% or 25% solution) without concurrent loop diuretics. Combination group: Received both albumin and a loop diuretic (furosemide, torsemide, or bumetanide) at any time during the ICU stay. Loop diuretic doses were converted to furosemide equivalents for analysis. Data Collection Data extraction was performed using Structured Query Language (SQL) via Navicat Premium software. Baseline characteristics, including demographics, comorbidities, severity scores (SOFA, SAPS II, GCS), vital signs, and laboratory values, were recorded within the first 24 hours of ICU admission. Treatments such as renal replacement therapy, vasopressor use, and crystalloid volume were also documented. Fluid balance was calculated as the net difference between crystalloid intake and urine output over the first 7 days of ICU stay. Outcomes The primary outcome was in-hospital mortality. Secondary outcomes included 30-day and 90-day mortality, ICU and hospital length of stay, duration of mechanical ventilation, and 7-day cumulative fluid balance. Statistical analysis Continuous variables were summarized as medians with interquartile ranges (IQRs), and categorical variables were presented as counts and percentages. To address potential confounding, propensity score matching (PSM) was performed in a 1:1 ratio without replacement, using a caliper width of 0.02. The propensity score was estimated using logistic regression that incorporated clinically relevant baseline variables. Covariate balance was assessed using standardized mean differences (SMD), with SMD < 0.1 indicating adequate balance. Between-group comparisons after matching were conducted using the chi-square test for categorical outcomes and the Mann–Whitney U test for continuous variables. Survival analysis was performed using Kaplan–Meier curves and log-rank tests. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Subgroup analyses were conducted for predefined patient strata, and interaction terms were tested. A dose–response analysis was performed by categorizing daily furosemide-equivalent doses into five levels. All analyses were two-tailed, with p < 0.05 considered statistically significant, and were performed using R version 4.3.1 and Stata 18.0. Results Baseline characteristics From the MIMIC-IV database, 16,043 adult septic patients requiring mechanical ventilation were initially identified. After applying exclusion criteria, a total of 4,805 patients were included in the overall cohort, of whom 1,172 received albumin alone and 3,633 received albumin in combination with loop diuretics. Following a 1:1 propensity score matching, 1,032 matched pairs (n = 2,064) were generated for comparative analysis. The study flow is illustrated in Fig. 1 . Before matching, significant imbalances were observed between the two groups regarding age, comorbidities, severity scores, and treatment profiles (Table 1 ). Patients receiving combination therapy were older (median age 68.3 vs. 62.3 years, p < 0.001) and exhibited a higher prevalence of congestive heart failure (33.7% vs. 20.6%, p < 0.001), but lower rates of chronic hepatic insufficiency (11.5% vs. 29.4%, p < 0.001) and renal replacement therapy (14.6% vs. 31.1%, p < 0.001). They also demonstrated lower illness severity, as indicated by SOFA (median 8 vs. 10, p < 0.001) and SAPS II scores (median 42 vs. 46, p < 0.001). Table 1 Baseline Characteristics of All Eligible Patients and the Propensity Score-Matched Cohort. All Patients (n = 4,805) Matched pairs (n = 2064) Characteristic Albumin Alone (n = 1,172) Albumin + Loop Diuretic (n = 3,633) P value SMD Albumin-alone (n = 1,032) Albumin + Loop Diuretic (n = 1,032) SMD Demographics Age, median (IQR), y 62.3 (52.9, 71.1) 68.3 (58.3, 77.1) < 0.001 0.374 63.4 (53.9, 72.4) 63.5 (52.1, 73.0) 0.065 Male sex, No. (%) 722 (61.6) 2164 (59.6) 0.22 0.042 626 (60.7) 621 (60.2) 0.008 White race, No. (%) 756 (64.5) 2529 (69.6) 0.001 0.109 682 (66.1) 648 (62.8) 0.059 Medicare insurance, No. (%) 482 (41.1) 1700 (46.8) < 0.001 0.114 435 (42.2) 428 (41.5) 0.026 Emergency admission, No. (%) 456 (38.9) 1116 (30.7) < 0.001 0.173 375 (36.3) 394 (38.2) 0.028 Clinical History, No. (%) Hypertension 808 (68.9) 2678 (73.7) 0.001 0.106 710 (68.8) 698 (67.6) 0.046 Congestive heart failure 241 (20.6) 1225 (33.7) < 0.001 0.299 225 (21.8) 226 (21.9) 0.005 Chronic hepatic insufficiency 344 (29.4) 417 (11.5) < 0.001 0.455 259 (25.1) 260 (25.2) 0.011 Chronic renal insufficiency 333 (28.4) 720 (19.8) < 0.001 0.202 267 (25.9) 261 (25.3) 0.018 Chronic pulmonary disease 281 (24.0) 1040 (28.6) 0.002 0.106 247 (23.9) 254 (24.6) 0.023 Diabetes 347 (29.6) 1148 (31.6) 0.20 0.043 298 (28.9) 302 (29.3) 0.004 Cancers 157 (13.4) 391 (10.8) 0.014 0.081 141 (13.7) 133 (12.9) 0.020 Severity Scores, median (IQR) Maximum SOFA score 10.0 (6.0, 14.0) 8.0 (6.0, 11.0) < 0.001 0.313 9.0 (6.0, 13.0) 9.0 (6.0, 13.0) 0.041 Maximum SAPII score 46.0 (37.0, 58.0) 42.0 (35.0, 52.0) < 0.001 0.242 46.0 (36.0, 57.0) 45.0 (36.0, 55.0) 0.056 Minimum GCS score 13.0 (7.0, 14.0) 12.0 (6.0, 14.0) 0.003 0.085 13.0 (7.0, 14.0) 13.0 (8.0, 14.0) 0.005 Clinical Status and Treatments, No. (%) Respiratory infection 393 (33.5) 1444 (39.7) < 0.001 0.129 354 (34.3) 367 (35.6) 0.020 Septic shock 546 (46.6) 1412 (38.9) < 0.001 0.157 465 (45.1) 444 (43.0) 0.041 Renal replacement therapy 364 (31.1) 529 (14.6) < 0.001 0.401 277 (26.8) 273 (26.5) 0.026 Laboratory Values, median (IQR) Minimum Pa0 2 /FiO 2 170.2 (98.0, 270.0) 158.6 (97.5, 236.0) < 0.001 0.169 170.0 (98.8, 266.6) 173.7 (102.9, 270.0) 0.032 Minimum albumin in ICU, g/dL 2.6 (2.2, 3.2) 2.8 (2.3, 3.3) 0.002 0.122 2.6 (2.2, 3.2) 2.7 (2.2, 3.2) 0.049 Treatments, median (IQR) Crystalloid volume on day 1, mL 4454.5 (2298.5, 7401.1) 4222.7 (2490.5, 6752.0) 0.14 0.085 4442.0 (2301.9, 7347.9) 4426.4 (2481.3, 7295.1) 0.010 Time to albumin infusion, h 19.0 (8.0, 55.0) 17.0 (8.0, 62.0) 0.97 0.004 19.0 (8.0, 53.5) 18.0 (8.0, 59.0) 0.003 Time to mechanical ventilation, h 3.0 (1.0, 8.0) 4.0 (1.9, 8.0) < 0.001 0.035 3.0 (1.0, 8.0) 3.5 (1.0, 9.0) 0.010 Total albumin amount in ICU, g 50.0 (25.0, 112.3) 50.0 (25.0, 125.0) < 0.001 0.041 50.0 (25.0, 100.0) 62.5 (25.0, 125.0) 0.036 Abbreviations: GCS, Glasgow Coma Scale; ICU, intensive care unit; IQR, interquartile range; SAPS II, Simplified Acute Physiology Score II; SMD, standardized mean difference; SOFA, Sequential Organ Failure Assessment. After matching, all baseline characteristics were well-balanced between the two groups, with standardized mean differences (SMDs) below 0.1 for all covariates (Table 1 ), indicating successful mitigation of confounding. Primary and secondary outcomes In the matched cohort, in-hospital mortality was significantly lower in the combination therapy group compared to the albumin-alone group (21.2% vs. 33.0%, p < 0.001) (Table 2 ). Similarly, 30-day mortality (22.4% vs. 32.8%, p < 0.001) and 90-day mortality (28.3% vs. 40.0%, p < 0.001) were markedly reduced in patients receiving combined albumin and loop diuretics. Although the combination group experienced longer ICU length of stay (median 7.5 vs. 4.5 days, p < 0.001) and hospital length of stay (median 16.1 vs. 12.0 days, p < 0.001), they achieved a substantially lower cumulative fluid balance over the first 7 days (median 1,462 mL vs. 4,304 mL, p < 0.001). The duration of mechanical ventilation did not differ significantly between the two groups (p = 0.058). Table 2 Primary and Secondary Outcomes in the Propensity Score-Matched Cohort Outcome Albumin Alone (n = 1,032) Albumin + Loop Diuretic (n = 1,032) P value Primary Outcome In-hospital mortality, No. (%) 341 (33.0) 219 (21.2) < 0.001 Secondary Outcomes 30-day mortality, No. (%) 338 (32.8) 231 (22.4) < 0.001 90-day mortality, No. (%) 413 (40.0) 292 (28.3) < 0.001 Length of Stay, median (IQR) Duration of mechanical ventilation, h 23.4 (10.0, 57.0) 23.0 (10.1, 78.9) 0.058 ICU stay, d 4.5 (2.4, 9.9) 7.5 (4.0, 13.9) < 0.001 Hospital stay, d 12.0 (6.7, 23.4) 16.1 (9.1, 27.0) < 0.001 Fluid balance in 7 days (ml), median(IQR) 4303.8 (272.3, 12877.8) 1462.2 (-3554.3, 8585.5) < 0.001 Abbreviations: ICU, intensive care unit; IQR, interquartile range. Subgroup analysis Subgroup analyses indicated that the survival benefit associated with combination therapy was consistent across most predefined subgroups, including those stratified by age, sex, SOFA score, septic shock status, and baseline renal function (Fig. 2 ). Notably, the magnitude of this benefit appeared more pronounced in patients without respiratory infections (HR 0.43, 95% CI 0.34–0.55) compared to those with respiratory infections (HR 0.58, 95% CI 0.47–0.72), demonstrating a significant interaction effect (p for interaction < 0.001). Kaplan-Meier survival curves Kaplan-Meier survival curves demonstrated a consistent separation favoring the combination therapy group both before and after matching (Fig. 3 A, B). Log-rank tests confirmed statistically significant survival benefits (p < 0.001). Effect of loop diuretic dose on in-hospital mortality A clear dose-response relationship was observed between the daily furosemide-equivalent dose and in-hospital mortality (Table 3 ). In the matched cohort, low-to-moderate diuretic doses (80 mg/day) conferred no survival advantage (HR 1.03, 95% CI 0.75–1.41, p = 0.858). The logit-transformed mortality proportions across dose categories are illustrated in Fig. 4 , demonstrating a U-shaped association, with the nadir of risk observed in the 20–40 mg/day range. Table 3 Hazard Ratios for In-Hospital Mortality According to Daily Furosemide-Equivalent Dose Before and After Propensity Score Matching. Group Before Matching (N = 4,805) After Matching (N = 2,064) HR (95% CI) P value HR (95% CI) P value Albumin alone 1.000(reference) - 1.000(reference) - Albumin + loop diuretic < 10 mg/day 0.49(0.42, 0.56) < 0.001 0.58(0.47, 0.72) < 0.001 10 ~ 20 mg/day 0.27(0.21, 0.36) < 0.001 0.41(0.25, 0.65) < 0.001 20 ~ 40 mg/day 0.31(0.25, 0.40) < 0.001 0.37(0.25, 0.55) < 0.001 40 ~ 80 mg/day 0.42(0.32, 0.54) 80 mg/day 0.62(0.50, 0.77) < 0.001 1.03(0.75, 1.41) 0.858 Abbreviations: CI, confidence interval; HR, hazard ratio. Discussion In this large-scale, retrospective, propensity score-matched cohort analysis of mechanically ventilated septic patients, the combination therapy of albumin and loop diuretics was associated with significantly lower in-hospital, 30-day, and 90-day mortality compared to albumin therapy alone. This survival benefit coincided with a substantially more negative cumulative fluid balance during the first week of ICU admission, despite longer lengths of stay in both the ICU and hospital. The treatment effect was consistent across most predefined subgroups, and a clear dose-response relationship was observed, where low-to-moderate furosemide-equivalent doses ( 80 mg/day) showed no significant survival advantage. The pathophysiological rationale for combining albumin with diuretics in critically ill patients, particularly in sepsis, is grounded in the complex interplay of hypoalbuminemia, fluid dynamics, and diuretic resistance [ 15 , 16 ]. A study found that in patients with acute lung injury and hypoalbuminemia, the combined use of albumin and furosemide can significantly improve the oxygenation index, achieve a greater negative fluid balance, and better maintain hemodynamic stability [ 17 ]. Sepsis is characterized by a complex interplay of systemic inflammation, endothelial dysfunction, and capillary leak, often necessitating aggressive fluid resuscitation, which can subsequently lead to fluid overload [ 18 , 19 ]. A positive fluid balance following initial resuscitation is a well-established independent predictor of mortality in septic patients [ 20 , 21 ]. A systematic review focusing on patients with severe sepsis or septic shock reached a similar conclusion, indicating that elevated fluid balance raised the risk of death by 70% [ 22 ]. Loop diuretics are a primary pharmacological tool for fluid removal; however, their efficacy can be diminished in critical illness due to factors such as reduced renal perfusion, altered pharmacokinetics, and hypoalbuminemia—a common comorbidity in sepsis that reduces drug delivery to the nephron [ 8 , 23 ]. The adjunctive use of albumin aims to counteract these limitations. By augmenting intravascular oncotic pressure and potentially improving renal perfusion, albumin may enhance the delivery and efficacy of protein-bound loop diuretics, such as furosemide [ 24 , 25 ]. Tie et al. (2024) found that albumin infusion in sepsis patients with serum levels < 30 g/L reduced mortality and acute kidney injury (AKI), but benefits plateaued above this threshold, suggesting a targeted therapeutic window [ 16 ]. Our finding of a markedly lower 7-day net fluid balance in the combination therapy group provides clinical support for this synergistic mechanism. The observed longer ICU and hospital stays in the combination group require careful interpretation. The observed adverse outcomes associated with albumin-loop diuretic co-administration may reflect a "survivor effect," wherein patients who respond effectively to fluid mobilization are more likely to survive the initial critical phase. At the same time, non-responders exhibit poorer outcomes due to underlying disease severity rather than the therapeutic intervention itself [ 26 ]. It also indicates the need for more proactive and prolonged management of fluid balance in these patients. Significantly, the duration of mechanical ventilation did not differ significantly, suggesting that prolonged stay was not primarily due to unresolved respiratory failure. This pattern has been noted in other critical care contexts where interventions that improve survival can be associated with extended recovery periods [ 27 ]. Dose-response analysis provides crucial clinical insights. The U-shaped relationship, demonstrating maximal benefit at furosemide-equivalent doses of 20–40 mg/day and diminished efficacy at higher doses, underscores the critical care principle that "more is not always better". This finding aligns with the conclusions reported by Wang B et al [ 10 ]. Low-to-moderate diuretic doses likely achieve effective decongestion while minimizing the risks associated with aggressive diuresis, such as intravascular volume depletion, electrolyte disturbances, and worsening renal function [ 28 – 30 ]. High-dose diuretic therapy may precipitate these complications, potentially offsetting the benefits of fluid removal, a concept increasingly recognized in heart failure and critical care nephrology [ 31 , 32 ]. This finding highlights the importance of careful titration and monitoring when administering diuretic therapy to septic patients. Subgroup analysis revealed a significant interaction based on the presence of respiratory infection, with a more pronounced mortality reduction in patients without a primary respiratory source. This may reflect differences in underlying pathophysiology or clinical management priorities. Patients with severe pneumonia or acute respiratory distress syndrome (ARDS) might have a different profile of vascular permeability and cardiopulmonary interaction, potentially altering the hemodynamic response to diuresis [ 33 , 34 ]. Alternatively, clinicians might be more cautious with diuretic use in patients with predominant lung injury. This interaction suggests that the benefit of combined albumin-diuretic therapy might be modulated by the sepsis phenotype, warranting further investigation into personalized fluid management strategies [ 16 , 34 ]. Several important limitations must be acknowledged. First, despite rigorous propensity score matching, the potential for residual confounding inherent to observational studies remains. Unmeasured variables, such as the precise clinical assessment of fluid overload (e.g., by ultrasonography) or hemodynamic monitoring data, could influence both treatment decisions and outcomes. Second, the single-center nature of the MIMIC-IV database may affect the generalizability of our findings. Third, our study lacks granular data on the timing, sequence, and specific clinical triggers for administering albumin and diuretics. The optimal protocol (e.g., concurrent infusion, timing relative to resuscitation) remains undefined and is critical for clinical application. Fourth, we were unable to comprehensively evaluate safety endpoints, such as acute kidney injury or electrolyte imbalances. Finally, these results are hypothesis-generating and necessitate confirmation in prospective, randomized controlled trials. Conclusion In this retrospective study of mechanically ventilated septic patients, combination therapy with albumin and loop diuretics was associated with significantly reduced short- and long-term mortality, as well as a more favorable fluid balance profile compared to albumin alone. The survival benefit was most evident with low-to-moderate diuretic doses, whereas high-dose therapy did not demonstrate any advantage. These findings support the notion that facilitating fluid mobilization during the critical phase of sepsis may improve patient outcomes and suggest a potential therapeutic role for adjunctive, moderately dosed loop diuretics in conjunction with albumin. Declarations Funding This work was supported by grants from the Sanming Project of Medicine in Shenzhen (SZSM202211016), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (No. SZGSP006), Medical Science and Technology Research Foundation of Guangdong Province (No. A2023354), Shenzhen Second People's Hospital Clinical Research Fund of Guangdong Province High-level Hospital Construction Projects (NO. 2023yjlcyj010), "New Medical Science" Teaching Reform Project of Guangdong Province (NO. 2023-119), The Gathering Apprentice Teaching Fund of Shenzhen University (NO. SZU-2023). Authors' contributions All authors had full access to the study data and ensured the integrity and accuracy of the data. Availability of data and materials Publicly available datasets were analyzed in this study. This data can be found at https://mimic.physionet.org. Ethics approval and consent to participate This study was approved by the Research Ethics Committee of Shenzhen Second People's Hospital (2025-797-01PJ). Considering the retrospective study design and depersonalization of the data, the Ethics Committee agreed to waive the requirement for written informed consent. Competing interests The authors declare that they have no competing interests. References Choudhary T, Upadhyaya P, Davis CM, et al. Derivation and validation of generalized sepsis-induced acute respiratory failure phenotypes among critically ill patients: a retrospective study. Crit Care. 2024;28(1):321. Luo M, He Q. Development of a prognostic nomogram for sepsis associated-acute respiratory failure patients on 30-day mortality in intensive care units: a retrospective cohort study. BMC Pulm Med. 2023;23(1):43. Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):775–87. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301–11. van Mourik N, Metske HA, Hofstra JJ, et al. Cumulative fluid balance predicts mortality and increases time on mechanical ventilation in ARDS patients: An observational cohort study. PLoS ONE. 2019;14(10):e0224563. Perren A, Brochard L. Managing the apparent and hidden difficulties of weaning from mechanical ventilation. Intensive Care Med. 2013;39(11):1885–95. Ruste M, Rodemund N, Subtil F et al. Association of cumulative fluid balance trajectories with haemodynamics, inflammation, and long-term mortality in critically ill patients with circulatory failure. Br J Anaesth 2025 Dec 1:S0007-0912(25)00788-3. Ferrari F, Zanza C, Tesauro M, et al. Clinical Pharmacology of Loop Diuretics in Critical Care. Clin Pharmacokinet. 2025;64(7):987–97. Soliman AR, Yousry A, Maamoun HA. Factors affecting response to furosemide stress test among critically ill hypoalbuminemic patients with AKI without prior albumin infusion. BMC Nephrol. 2025;26(1):664. Wang B, Sha W, Gui S, et al. Efficacy of albumin and loop diuretic Co-administration in reducing mortality among septic patients with hypoalbuminemia. Eur J Pharmacol. 2025;999:177692. Wiedermann CJ. Human Albumin Infusion in Critically Ill and Perioperative Patients: Narrative Rapid Review of Meta-Analyses from the Last Five Years. J Clin Med. 2023;12(18):5919. Macedo E, Karl B, Lee E, et al. A randomized trial of albumin infusion to prevent intradialytic hypotension in hospitalized hypoalbuminemic patients. Crit Care. 2021;25(1):18. Tufoni M, Zaccherini G, Caraceni P, et al. Albumin: Indications in chronic liver disease. United Eur Gastroenterol J. 2020;8(5):528–35. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Jama Feb. 2016;23(8):801–10. Zhou S, Zeng Z, Wei H, et al. Early combination of albumin with crystalloids administration might be beneficial for the survival of septic patients: a retrospective analysis from MIMIC-IV database. Ann Intensive Care. 2021;11(1):42. Tie X, Zhao Y, Sun T, et al. Associations between serum albumin level trajectories and clinical outcomes in sepsis patients in ICU: insights from longitudinal group trajectory modeling. Front Nutr. 2024;11:1433544. Mangialardi RJ, Wheeler AP, Dupont WD, et al. Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury. Crit Care Med. 2002;30(10):2175–82. Dolmatova EV, Wang K, Mandavilli R, et al. The effects of sepsis on endothelium and clinical implications. Cardiovasc Res. 2021;117(1):60–73. Mira JC, Gentile LF, Mathias BJ, et al. Sepsis Pathophysiology, Chronic Critical Illness, and Persistent Inflammation-Immunosuppression and Catabolism Syndrome. Crit Care Med. 2017;45(2):253–62. Acheampong A, Vincent JL. A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit Care. 2015;19:251. Yoo MS, Zhu S, Lu Y, et al. Association of Positive Fluid Balance at Discharge After Sepsis Management With 30-Day Readmission. JAMA Netw Open. 2021;4(6):e216105. Palazzuoli A, Ruocco G, Ronco C, et al. Loop diuretics in acute heart failure: beyond the decongestive relief for the kidney. Crit Care. 2015;19:296. Mahmoodpoor A, Zahedi S, Pourakbar A, et al. Efficacy of furosemide-albumin compared with furosemide in critically ill hypoalbuminemia patients admitted to intensive care unit: a prospective randomized clinical trial. Daru. 2020;28(1):263–9. Charokopos A, Griffin M, Rao VS, et al. Serum and Urine Albumin and Response to Loop Diuretics in Heart Failure. Clin J Am Soc Nephrol. 2019;14(5):712–8. Shen Y, Zhang W,Shen Y. Early diuretic use and mortality in critically ill patients with vasopressor support: a propensity score-matching analysis. Crit Care. 2019;23(1):9. Zhang Z, Ho KM, Gu H, et al. Defining persistent critical illness based on growth trajectories in patients with sepsis. Crit Care. 2020;24(1):57. Meekers E, Dauw J, Martens P, et al. Renal function and decongestion with acetazolamide in acute decompensated heart failure: the ADVOR trial. Eur Heart J. 2023;44(37):3672–82. Testani JM, Chen J, McCauley BD, et al. Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation. 2010;122(3):265–72. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364(9):797–805. Brisco-Bacik MA, Ter Maaten JM, Houser SR, et al. Outcomes Associated With a Strategy of Adjuvant Metolazone or High-Dose Loop Diuretics in Acute Decompensated Heart Failure: A Propensity Analysis. J Am Heart Assoc. 2018;7(18):e009149. Hanberg JS, Tang WHW, Wilson FP, et al. An exploratory analysis of the competing effects of aggressive decongestion and high-dose loop diuretic therapy in the DOSE trial. Int J Cardiol. 2017;241:277–82. Zornitzki L, Bornstein G. Potential role for furosemide in the treatment of acute respiratory distress syndrome (ARDS) and an unusual presentation of pulmonary embolism in a complex patient. BMJ Case Rep. 2020;13(8):e235010. Seitz KP, Caldwell ES, Hough CL. Fluid management in ARDS: an evaluation of current practice and the association between early diuretic use and hospital mortality. J Intensive Care. 2020;8:78. Gabarre P, Desnos C, Morin A, et al. Albumin versus saline infusion for sepsis-related peripheral tissue hypoperfusion: a proof-of-concept prospective study. Crit Care. 2024;28(1):43. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 06 Feb, 2026 Editor invited by journal 19 Jan, 2026 Editor assigned by journal 19 Jan, 2026 Submission checks completed at journal 19 Jan, 2026 First submitted to journal 15 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8607908","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":587843760,"identity":"4b085f7f-9e3a-42f1-a54b-a3206094f65e","order_by":0,"name":"Xisi He","email":"","orcid":"","institution":"Shenzhen Second People's Hospital \u0026 First Affiliated hospital of Shenzhen University","correspondingAuthor":false,"prefix":"","firstName":"Xisi","middleName":"","lastName":"He","suffix":""},{"id":587843761,"identity":"f0170e32-9681-4868-81c0-423b3c204c02","order_by":1,"name":"Shuiqing Gui","email":"","orcid":"","institution":"Shenzhen Second People's Hospital \u0026 First Affiliated hospital of Shenzhen University","correspondingAuthor":false,"prefix":"","firstName":"Shuiqing","middleName":"","lastName":"Gui","suffix":""},{"id":587843762,"identity":"adc7b89c-8a49-4fe6-a565-d5f39597565d","order_by":2,"name":"Zhiye Zou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvklEQVRIiWNgGAWjYJACZgYDBgZ+ZubDD0jTItnOlmZAghYgMDjPoyBBlHL59h7jzwUFh+WMD/MALauxiSaohbHnjIHxDIPDxmaHeQ88YDiWlttA0FESOQbJPAaHE7cd5kswYGw4TFgLG1DLYaCW+s3NPAYSRGnhkcgxBCo+nGDATKwWCZ5jxUDF6YYzDgMDOYEYv8i3N2/+zPPHWp6///DhBx9qbAhrgYJmCJVApHIQqCNB7SgYBaNgFIw4AADgZjfaFjP1AAAAAABJRU5ErkJggg==","orcid":"","institution":"Shenzhen Second People's Hospital \u0026 First Affiliated hospital of Shenzhen University","correspondingAuthor":true,"prefix":"","firstName":"Zhiye","middleName":"","lastName":"Zou","suffix":""}],"badges":[],"createdAt":"2026-01-15 07:23:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8607908/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8607908/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102745853,"identity":"58262546-88fd-4014-aaf2-1c7860abc51d","added_by":"auto","created_at":"2026-02-16 08:54:22","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":123637,"visible":true,"origin":"","legend":"\u003cp\u003eFlow Chart of the Study\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8607908/v1/c72053ada88f3b32eb2e5a60.jpg"},{"id":102440210,"identity":"d2d35cbf-62d8-462e-9261-fdf93af374fd","added_by":"auto","created_at":"2026-02-11 16:46:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":105164,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup Analysis of the Association Between In-Hospital Mortality and Combined Albumin and Loop Diuretic Therapy\u003c/p\u003e\n\u003cp\u003e*We adjusted all the variables in Table 1.\u003c/p\u003e\n\u003cp\u003eThe association between combined loop diuretic use and mortality remained significant in all subgroups, except in the subgroup of patients without respiratory infections.\u003c/p\u003e\n\u003cp\u003ePatients with respiratory infections (HR=0.58) showed a 42% reduction in in-hospital mortality risk in the combined loop diuretic group compared to the albumin-only group. Patients without respiratory infection (HR=0.43) showed that the risk of death in the in-hospital setting was 57% lower in the combined loop diuretic group than in the albumin-only group. In the last column, P for interaction was less than 0.001, indicating a a significant difference in the relationship between combined loop diuretic treatment and death between patients with and without respiratory infection. That is to say, the previous differences of 0.58 and 0.43 in HR were statistically significant, and the relationship between loop diuretic treatment and death may be different in patients with and without respiratory infections.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8607908/v1/0b9842fb95bea96da99dfb0f.png"},{"id":102440211,"identity":"fe356ab0-e3dd-48b3-8dcb-16fea7cbcab3","added_by":"auto","created_at":"2026-02-11 16:46:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":125346,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier Survival Curves of Two Groups Before (A) and After (B) PSM\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8607908/v1/a990b9d185ad3113164657b4.png"},{"id":102440208,"identity":"ace9d6a7-ad7f-4f44-80fa-e4134399f597","added_by":"auto","created_at":"2026-02-11 16:46:33","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":52210,"visible":true,"origin":"","legend":"\u003cp\u003eLogit-Transformed Proportions of In-Hospital Mortality According to Daily Furosemide-Equivalent Dose\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8607908/v1/6ae8a2ede3042c53bde9d43e.png"},{"id":102751641,"identity":"41a66ad3-fc5e-454e-bcd6-b961032161ae","added_by":"auto","created_at":"2026-02-16 09:26:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1519824,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8607908/v1/8c5291a2-d809-4dd3-ae31-fdc7770ce673.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Combination Therapy of Albumin and Loop Diuretics May Improve Survival in Patients with Sepsis Receiving Mechanical Ventilation: A Propensity Score Matched Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSepsis remains a leading cause of morbidity and mortality in intensive care units (ICUs), frequently complicated by acute respiratory failure that necessitates invasive mechanical ventilation (MV) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Managing fluid balance in this critically ill population presents a persistent challenge. While early fluid resuscitation is fundamental in septic shock [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], accumulating evidence suggests that a positive cumulative fluid balance following initial stabilization is associated with prolonged mechanical ventilation, extended ICU stays, and increased mortality [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this context, strategies to facilitate fluid mobilization during the post-resuscitation phase are of substantial clinical interest. Loop diuretics are commonly employed to promote diuresis; however, their efficacy may be limited in critically ill patients due to factors such as impaired renal perfusion and altered pharmacokinetics [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Concurrent hypoalbuminemia, often observed in severe sepsis, can further attenuate the diuretic response by reducing intravascular oncotic pressure and decreasing the renal delivery of protein-bound loop diuretics [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].The concomitant administration of albumin with loop diuretics has been proposed as a strategy to potentially enhance diuretic efficacy. Theoretically, albumin infusion may improve intravascular volume status and renal perfusion, thereby increasing the delivery of diuretics to their site of action in the nephron [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Although this combined approach is sometimes utilized in clinical practice, its impact on meaningful clinical outcomes, particularly survival in mechanically ventilated septic patients, is not well established. Robust evidence from large-scale studies is lacking.\u003c/p\u003e \u003cp\u003eConsequently, we conducted a retrospective cohort study utilizing data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Our primary objective was to investigate whether the combination of albumin and loop diuretics, as opposed to albumin alone, is associated with a reduction in in-hospital mortality among adult septic patients requiring mechanical ventilation. Secondary objectives included evaluating the effects on 30- and 90-day mortality, length of stay, fluid balance, and exploring potential dose-response relationships.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData source and study design\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study utilized data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, version 2.0 (available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://physionet.org/content/mimiciv/2.0/\u003c/span\u003e\u003cspan address=\"https://physionet.org/content/mimiciv/2.0/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The database contains de-identified clinical information from 76,943 ICU admissions at Beth Israel Deaconess Medical Center (BIDMC) between 2008 and 2019. Access to the database was authorized after completion of the Collaborative Institutional Training Initiative (CITI) program (certification number for author ZYZ: 59729494). The study protocol was approved by the Research Ethics Committee of Shenzhen Second People\u0026rsquo;s Hospital. All data were handled in compliance with HIPAA regulations, and the study adhered to the STROBE guidelines for observational research.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy population\u003c/h3\u003e\n\u003cp\u003eAdult patients (aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years) with sepsis requiring invasive mechanical ventilation were included. Sepsis was defined according to the Sepsis-3 criteria, based on a Sequential Organ Failure Assessment (SOFA) score increase of 2 points or more with suspected or confirmed infection [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Patients were excluded if they were younger than 18 years or older than 90 years, stayed in the ICU for less than 24 hours or more than 100 days, died within the first 24 hours of ICU admission, had sepsis onset before ICU admission (12 hours) or after ICU admission (24 hours), or had received albumin or loop diuretics before ICU admission. For patients with multiple ICU admissions during the same hospitalization, only data from the first ICU admission were included.\u003c/p\u003e\n\u003ch3\u003eExposure and comparator\u003c/h3\u003e\n\u003cp\u003ePatients were classified into two groups based on the treatment they received during their stay in the ICU. Albumin-alone group: Received albumin (5% or 25% solution) without concurrent loop diuretics. Combination group: Received both albumin and a loop diuretic (furosemide, torsemide, or bumetanide) at any time during the ICU stay. Loop diuretic doses were converted to furosemide equivalents for analysis.\u003c/p\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eData extraction was performed using Structured Query Language (SQL) via Navicat Premium software. Baseline characteristics, including demographics, comorbidities, severity scores (SOFA, SAPS II, GCS), vital signs, and laboratory values, were recorded within the first 24 hours of ICU admission. Treatments such as renal replacement therapy, vasopressor use, and crystalloid volume were also documented. Fluid balance was calculated as the net difference between crystalloid intake and urine output over the first 7 days of ICU stay.\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was in-hospital mortality. Secondary outcomes included 30-day and 90-day mortality, ICU and hospital length of stay, duration of mechanical ventilation, and 7-day cumulative fluid balance.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were summarized as medians with interquartile ranges (IQRs), and categorical variables were presented as counts and percentages. To address potential confounding, propensity score matching (PSM) was performed in a 1:1 ratio without replacement, using a caliper width of 0.02. The propensity score was estimated using logistic regression that incorporated clinically relevant baseline variables. Covariate balance was assessed using standardized mean differences (SMD), with SMD\u0026thinsp;\u0026lt;\u0026thinsp;0.1 indicating adequate balance. Between-group comparisons after matching were conducted using the chi-square test for categorical outcomes and the Mann\u0026ndash;Whitney U test for continuous variables. Survival analysis was performed using Kaplan\u0026ndash;Meier curves and log-rank tests. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Subgroup analyses were conducted for predefined patient strata, and interaction terms were tested. A dose\u0026ndash;response analysis was performed by categorizing daily furosemide-equivalent doses into five levels. All analyses were two-tailed, with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered statistically significant, and were performed using R version 4.3.1 and Stata 18.0.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics\u003c/h2\u003e \u003cp\u003eFrom the MIMIC-IV database, 16,043 adult septic patients requiring mechanical ventilation were initially identified. After applying exclusion criteria, a total of 4,805 patients were included in the overall cohort, of whom 1,172 received albumin alone and 3,633 received albumin in combination with loop diuretics. Following a 1:1 propensity score matching, 1,032 matched pairs (n\u0026thinsp;=\u0026thinsp;2,064) were generated for comparative analysis. The study flow is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBefore matching, significant imbalances were observed between the two groups regarding age, comorbidities, severity scores, and treatment profiles (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Patients receiving combination therapy were older (median age 68.3 vs. 62.3 years, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and exhibited a higher prevalence of congestive heart failure (33.7% vs. 20.6%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), but lower rates of chronic hepatic insufficiency (11.5% vs. 29.4%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and renal replacement therapy (14.6% vs. 31.1%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). They also demonstrated lower illness severity, as indicated by SOFA (median 8 vs. 10, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and SAPS II scores (median 42 vs. 46, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\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 All Eligible Patients and the Propensity Score-Matched Cohort.\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=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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\u003eAll Patients (n\u0026thinsp;=\u0026thinsp;4,805)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c9\" namest=\"c7\"\u003e \u003cp\u003eMatched pairs (n\u0026thinsp;=\u0026thinsp;2064)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlbumin Alone\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1,172)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlbumin\u0026thinsp;+\u0026thinsp;Loop Diuretic\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;3,633)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSMD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAlbumin-alone\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1,032)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAlbumin\u0026thinsp;+\u0026thinsp;Loop Diuretic\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1,032)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSMD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median (IQR), y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e62.3 (52.9, 71.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e68.3 (58.3, 77.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.374\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e63.4 (53.9, 72.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e63.5 (52.1, 73.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.065\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale sex, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e722 (61.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2164 (59.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e626 (60.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e621 (60.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite race, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e756 (64.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2529 (69.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e682 (66.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e648 (62.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.059\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedicare insurance, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e482 (41.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1700 (46.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e435 (42.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e428 (41.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmergency admission, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e456 (38.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1116 (30.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.173\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e375 (36.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e394 (38.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical History, No. (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\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\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e808 (68.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2678 (73.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e710 (68.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e698 (67.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongestive heart failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e241 (20.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1225 (33.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.299\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e225 (21.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e226 (21.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic hepatic insufficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e344 (29.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e417 (11.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.455\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e259 (25.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e260 (25.2)\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\u003eChronic renal insufficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e333 (28.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e720 (19.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.202\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e267 (25.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e261 (25.3)\u003c/p\u003e \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\u003eChronic pulmonary disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e281 (24.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1040 (28.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e247 (23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e254 (24.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e347 (29.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1148 (31.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.043\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e298 (28.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e302 (29.3)\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\u003eCancers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e157 (13.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e391 (10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.081\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e141 (13.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e133 (12.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSeverity Scores, median (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\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\u003eMaximum SOFA score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10.0 (6.0, 14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.0 (6.0, 11.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.313\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e9.0 (6.0, 13.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.0 (6.0, 13.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaximum SAPII score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46.0 (37.0, 58.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e42.0 (35.0, 52.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.242\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e46.0 (36.0, 57.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e45.0 (36.0, 55.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMinimum GCS score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13.0 (7.0, 14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.0 (6.0, 14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.085\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e13.0 (7.0, 14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e13.0 (8.0, 14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical Status and Treatments, No. (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\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\u003eRespiratory infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e393 (33.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1444 (39.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e354 (34.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e367 (35.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeptic shock\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e546 (46.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1412 (38.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.157\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e465 (45.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e444 (43.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal replacement therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e364 (31.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e529 (14.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.401\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e277 (26.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e273 (26.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLaboratory Values, median (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\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\u003eMinimum Pa0\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e170.2 (98.0, 270.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e158.6 (97.5, 236.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.169\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e170.0 (98.8, 266.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e173.7 (102.9, 270.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMinimum albumin in ICU, g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.6 (2.2, 3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.8 (2.3, 3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.6 (2.2, 3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.7 (2.2, 3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTreatments, median (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\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\u003eCrystalloid volume on day 1, mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4454.5 (2298.5, 7401.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4222.7 (2490.5, 6752.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.085\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e4442.0 (2301.9, 7347.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4426.4 (2481.3, 7295.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to albumin infusion, h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19.0 (8.0, 55.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17.0 (8.0, 62.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e19.0 (8.0, 53.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e18.0 (8.0, 59.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to mechanical ventilation, h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.0 (1.0, 8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.0 (1.9, 8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.0 (1.0, 8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.5 (1.0, 9.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal albumin amount in ICU, g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50.0 (25.0, 112.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50.0 (25.0, 125.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e50.0 (25.0, 100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e62.5 (25.0, 125.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eAbbreviations: GCS, Glasgow Coma Scale; ICU, intensive care unit; IQR, interquartile range; SAPS II, Simplified Acute Physiology Score II; SMD, standardized mean difference; SOFA, Sequential Organ Failure Assessment.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAfter matching, all baseline characteristics were well-balanced between the two groups, with standardized mean differences (SMDs) below 0.1 for all covariates (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), indicating successful mitigation of confounding.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePrimary and secondary outcomes\u003c/h2\u003e \u003cp\u003eIn the matched cohort, in-hospital mortality was significantly lower in the combination therapy group compared to the albumin-alone group (21.2% vs. 33.0%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Similarly, 30-day mortality (22.4% vs. 32.8%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and 90-day mortality (28.3% vs. 40.0%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were markedly reduced in patients receiving combined albumin and loop diuretics. Although the combination group experienced longer ICU length of stay (median 7.5 vs. 4.5 days, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and hospital length of stay (median 16.1 vs. 12.0 days, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), they achieved a substantially lower cumulative fluid balance over the first 7 days (median 1,462 mL vs. 4,304 mL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The duration of mechanical ventilation did not differ significantly between the two groups (p\u0026thinsp;=\u0026thinsp;0.058).\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 in the Propensity Score-Matched Cohort\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlbumin Alone (n\u0026thinsp;=\u0026thinsp;1,032)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAlbumin\u0026thinsp;+\u0026thinsp;Loop Diuretic (n\u0026thinsp;=\u0026thinsp;1,032)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary Outcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn-hospital mortality, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e341 (33.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e219 (21.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" 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\u003e\u003cb\u003eSecondary Outcomes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30-day mortality, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e338 (32.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e231 (22.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" 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\u003e90-day mortality, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e413 (40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e292 (28.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" 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\u003e\u003cb\u003eLength of Stay, median (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of mechanical ventilation, h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23.4 (10.0, 57.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23.0 (10.1, 78.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU stay, d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.5 (2.4, 9.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.5 (4.0, 13.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" 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\u003eHospital stay, d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.0 (6.7, 23.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16.1 (9.1, 27.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" 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\u003e\u003cb\u003eFluid balance in 7 days (ml), median(IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4303.8 (272.3, 12877.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1462.2 (-3554.3, 8585.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" 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\"\u003eAbbreviations: ICU, intensive care unit; IQR, interquartile range.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup analysis\u003c/h2\u003e \u003cp\u003eSubgroup analyses indicated that the survival benefit associated with combination therapy was consistent across most predefined subgroups, including those stratified by age, sex, SOFA score, septic shock status, and baseline renal function (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Notably, the magnitude of this benefit appeared more pronounced in patients without respiratory infections (HR 0.43, 95% CI 0.34\u0026ndash;0.55) compared to those with respiratory infections (HR 0.58, 95% CI 0.47\u0026ndash;0.72), demonstrating a significant interaction effect (p for interaction\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eKaplan-Meier survival curves\u003c/h2\u003e \u003cp\u003eKaplan-Meier survival curves demonstrated a consistent separation favoring the combination therapy group both before and after matching (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, B). Log-rank tests confirmed statistically significant survival benefits (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eEffect of loop diuretic dose on in-hospital mortality\u003c/h2\u003e \u003cp\u003eA clear dose-response relationship was observed between the daily furosemide-equivalent dose and in-hospital mortality (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In the matched cohort, low-to-moderate diuretic doses (80 mg/day) conferred no survival advantage (HR 1.03, 95% CI 0.75\u0026ndash;1.41, p\u0026thinsp;=\u0026thinsp;0.858). The logit-transformed mortality proportions across dose categories are illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, demonstrating a U-shaped association, with the nadir of risk observed in the 20\u0026ndash;40 mg/day range.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHazard Ratios for In-Hospital Mortality According to Daily Furosemide-Equivalent Dose Before and After Propensity Score Matching.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore Matching\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;4,805)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAfter Matching\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;2,064)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.000(reference)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000(reference)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin\u0026thinsp;+\u0026thinsp;loop diuretic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;10 mg/day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.49(0.42, 0.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.58(0.47, 0.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\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\u003e10\u0026thinsp;~\u0026thinsp;20 mg/day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.27(0.21, 0.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.41(0.25, 0.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\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\u003e20\u0026thinsp;~\u0026thinsp;40 mg/day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.31(0.25, 0.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.37(0.25, 0.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\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\u003e40\u0026thinsp;~\u0026thinsp;80 mg/day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.42(0.32, 0.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.69(0.46, 1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;80 mg/day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.62(0.50, 0.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.03(0.75, 1.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.858\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eAbbreviations: CI, confidence interval; HR, hazard ratio.\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"},{"header":"Discussion","content":"\u003cp\u003eIn this large-scale, retrospective, propensity score-matched cohort analysis of mechanically ventilated septic patients, the combination therapy of albumin and loop diuretics was associated with significantly lower in-hospital, 30-day, and 90-day mortality compared to albumin therapy alone. This survival benefit coincided with a substantially more negative cumulative fluid balance during the first week of ICU admission, despite longer lengths of stay in both the ICU and hospital. The treatment effect was consistent across most predefined subgroups, and a clear dose-response relationship was observed, where low-to-moderate furosemide-equivalent doses (\u0026lt;\u0026thinsp;40 mg/day) conferred the most significant mortality reduction, while higher doses (\u0026gt;\u0026thinsp;80 mg/day) showed no significant survival advantage.\u003c/p\u003e \u003cp\u003eThe pathophysiological rationale for combining albumin with diuretics in critically ill patients, particularly in sepsis, is grounded in the complex interplay of hypoalbuminemia, fluid dynamics, and diuretic resistance [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. A study found that in patients with acute lung injury and hypoalbuminemia, the combined use of albumin and furosemide can significantly improve the oxygenation index, achieve a greater negative fluid balance, and better maintain hemodynamic stability [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Sepsis is characterized by a complex interplay of systemic inflammation, endothelial dysfunction, and capillary leak, often necessitating aggressive fluid resuscitation, which can subsequently lead to fluid overload [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A positive fluid balance following initial resuscitation is a well-established independent predictor of mortality in septic patients [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A systematic review focusing on patients with severe sepsis or septic shock reached a similar conclusion, indicating that elevated fluid balance raised the risk of death by 70% [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Loop diuretics are a primary pharmacological tool for fluid removal; however, their efficacy can be diminished in critical illness due to factors such as reduced renal perfusion, altered pharmacokinetics, and hypoalbuminemia\u0026mdash;a common comorbidity in sepsis that reduces drug delivery to the nephron [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The adjunctive use of albumin aims to counteract these limitations. By augmenting intravascular oncotic pressure and potentially improving renal perfusion, albumin may enhance the delivery and efficacy of protein-bound loop diuretics, such as furosemide [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Tie et al. (2024) found that albumin infusion in sepsis patients with serum levels\u0026thinsp;\u0026lt;\u0026thinsp;30 g/L reduced mortality and acute kidney injury (AKI), but benefits plateaued above this threshold, suggesting a targeted therapeutic window [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Our finding of a markedly lower 7-day net fluid balance in the combination therapy group provides clinical support for this synergistic mechanism.\u003c/p\u003e \u003cp\u003eThe observed longer ICU and hospital stays in the combination group require careful interpretation. The observed adverse outcomes associated with albumin-loop diuretic co-administration may reflect a \"survivor effect,\" wherein patients who respond effectively to fluid mobilization are more likely to survive the initial critical phase. At the same time, non-responders exhibit poorer outcomes due to underlying disease severity rather than the therapeutic intervention itself [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. It also indicates the need for more proactive and prolonged management of fluid balance in these patients. Significantly, the duration of mechanical ventilation did not differ significantly, suggesting that prolonged stay was not primarily due to unresolved respiratory failure. This pattern has been noted in other critical care contexts where interventions that improve survival can be associated with extended recovery periods [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDose-response analysis provides crucial clinical insights. The U-shaped relationship, demonstrating maximal benefit at furosemide-equivalent doses of 20\u0026ndash;40 mg/day and diminished efficacy at higher doses, underscores the critical care principle that \"more is not always better\". This finding aligns with the conclusions reported by Wang B et al [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLow-to-moderate diuretic doses likely achieve effective decongestion while minimizing the risks associated with aggressive diuresis, such as intravascular volume depletion, electrolyte disturbances, and worsening renal function [\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. High-dose diuretic therapy may precipitate these complications, potentially offsetting the benefits of fluid removal, a concept increasingly recognized in heart failure and critical care nephrology [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. This finding highlights the importance of careful titration and monitoring when administering diuretic therapy to septic patients.\u003c/p\u003e \u003cp\u003eSubgroup analysis revealed a significant interaction based on the presence of respiratory infection, with a more pronounced mortality reduction in patients without a primary respiratory source. This may reflect differences in underlying pathophysiology or clinical management priorities. Patients with severe pneumonia or acute respiratory distress syndrome (ARDS) might have a different profile of vascular permeability and cardiopulmonary interaction, potentially altering the hemodynamic response to diuresis [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Alternatively, clinicians might be more cautious with diuretic use in patients with predominant lung injury. This interaction suggests that the benefit of combined albumin-diuretic therapy might be modulated by the sepsis phenotype, warranting further investigation into personalized fluid management strategies [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral important limitations must be acknowledged. First, despite rigorous propensity score matching, the potential for residual confounding inherent to observational studies remains. Unmeasured variables, such as the precise clinical assessment of fluid overload (e.g., by ultrasonography) or hemodynamic monitoring data, could influence both treatment decisions and outcomes. Second, the single-center nature of the MIMIC-IV database may affect the generalizability of our findings. Third, our study lacks granular data on the timing, sequence, and specific clinical triggers for administering albumin and diuretics. The optimal protocol (e.g., concurrent infusion, timing relative to resuscitation) remains undefined and is critical for clinical application. Fourth, we were unable to comprehensively evaluate safety endpoints, such as acute kidney injury or electrolyte imbalances. Finally, these results are hypothesis-generating and necessitate confirmation in prospective, randomized controlled trials.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this retrospective study of mechanically ventilated septic patients, combination therapy with albumin and loop diuretics was associated with significantly reduced short- and long-term mortality, as well as a more favorable fluid balance profile compared to albumin alone. The survival benefit was most evident with low-to-moderate diuretic doses, whereas high-dose therapy did not demonstrate any advantage. These findings support the notion that facilitating fluid mobilization during the critical phase of sepsis may improve patient outcomes and suggest a potential therapeutic role for adjunctive, moderately dosed loop diuretics in conjunction with albumin.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by grants from the Sanming Project of Medicine in Shenzhen (SZSM202211016), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (No. SZGSP006), Medical Science and Technology Research Foundation of Guangdong Province (No. A2023354), Shenzhen Second People's Hospital Clinical Research Fund of Guangdong Province High-level Hospital Construction Projects (NO. 2023yjlcyj010), \"New Medical Science\" Teaching Reform Project of Guangdong Province (NO. 2023-119), The Gathering Apprentice Teaching Fund of Shenzhen University (NO. SZU-2023).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors had full access to the study data and ensured the integrity and accuracy of the data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePublicly available datasets were analyzed in this study. This data can be found at https://mimic.physionet.org.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Research Ethics Committee of Shenzhen Second People's Hospital (2025-797-01PJ). Considering the retrospective study design and depersonalization of the data, the Ethics Committee agreed to waive the requirement for written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChoudhary T, Upadhyaya P, Davis CM, et al. Derivation and validation of generalized sepsis-induced acute respiratory failure phenotypes among critically ill patients: a retrospective study. Crit Care. 2024;28(1):321.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuo M, He Q. Development of a prognostic nomogram for sepsis associated-acute respiratory failure patients on 30-day mortality in intensive care units: a retrospective cohort study. BMC Pulm Med. 2023;23(1):43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShankar-Hari M, Phillips GS, Levy ML, et al. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):775\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Mourik N, Metske HA, Hofstra JJ, et al. Cumulative fluid balance predicts mortality and increases time on mechanical ventilation in ARDS patients: An observational cohort study. PLoS ONE. 2019;14(10):e0224563.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerren A, Brochard L. Managing the apparent and hidden difficulties of weaning from mechanical ventilation. Intensive Care Med. 2013;39(11):1885\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRuste M, Rodemund N, Subtil F et al. Association of cumulative fluid balance trajectories with haemodynamics, inflammation, and long-term mortality in critically ill patients with circulatory failure. Br J Anaesth 2025 Dec 1:S0007-0912(25)00788-3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerrari F, Zanza C, Tesauro M, et al. Clinical Pharmacology of Loop Diuretics in Critical Care. Clin Pharmacokinet. 2025;64(7):987\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoliman AR, Yousry A, Maamoun HA. Factors affecting response to furosemide stress test among critically ill hypoalbuminemic patients with AKI without prior albumin infusion. BMC Nephrol. 2025;26(1):664.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang B, Sha W, Gui S, et al. Efficacy of albumin and loop diuretic Co-administration in reducing mortality among septic patients with hypoalbuminemia. Eur J Pharmacol. 2025;999:177692.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWiedermann CJ. Human Albumin Infusion in Critically Ill and Perioperative Patients: Narrative Rapid Review of Meta-Analyses from the Last Five Years. J Clin Med. 2023;12(18):5919.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMacedo E, Karl B, Lee E, et al. A randomized trial of albumin infusion to prevent intradialytic hypotension in hospitalized hypoalbuminemic patients. Crit Care. 2021;25(1):18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTufoni M, Zaccherini G, Caraceni P, et al. Albumin: Indications in chronic liver disease. United Eur Gastroenterol J. 2020;8(5):528\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSinger M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Jama Feb. 2016;23(8):801\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou S, Zeng Z, Wei H, et al. Early combination of albumin with crystalloids administration might be beneficial for the survival of septic patients: a retrospective analysis from MIMIC-IV database. Ann Intensive Care. 2021;11(1):42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTie X, Zhao Y, Sun T, et al. Associations between serum albumin level trajectories and clinical outcomes in sepsis patients in ICU: insights from longitudinal group trajectory modeling. Front Nutr. 2024;11:1433544.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMangialardi RJ, Wheeler AP, Dupont WD, et al. Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury. Crit Care Med. 2002;30(10):2175\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDolmatova EV, Wang K, Mandavilli R, et al. The effects of sepsis on endothelium and clinical implications. Cardiovasc Res. 2021;117(1):60\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMira JC, Gentile LF, Mathias BJ, et al. Sepsis Pathophysiology, Chronic Critical Illness, and Persistent Inflammation-Immunosuppression and Catabolism Syndrome. Crit Care Med. 2017;45(2):253\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAcheampong A, Vincent JL. A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit Care. 2015;19:251.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoo MS, Zhu S, Lu Y, et al. Association of Positive Fluid Balance at Discharge After Sepsis Management With 30-Day Readmission. JAMA Netw Open. 2021;4(6):e216105.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalazzuoli A, Ruocco G, Ronco C, et al. Loop diuretics in acute heart failure: beyond the decongestive relief for the kidney. Crit Care. 2015;19:296.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahmoodpoor A, Zahedi S, Pourakbar A, et al. Efficacy of furosemide-albumin compared with furosemide in critically ill hypoalbuminemia patients admitted to intensive care unit: a prospective randomized clinical trial. Daru. 2020;28(1):263\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCharokopos A, Griffin M, Rao VS, et al. Serum and Urine Albumin and Response to Loop Diuretics in Heart Failure. Clin J Am Soc Nephrol. 2019;14(5):712\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShen Y, Zhang W,Shen Y. Early diuretic use and mortality in critically ill patients with vasopressor support: a propensity score-matching analysis. Crit Care. 2019;23(1):9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Z, Ho KM, Gu H, et al. Defining persistent critical illness based on growth trajectories in patients with sepsis. Crit Care. 2020;24(1):57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeekers E, Dauw J, Martens P, et al. Renal function and decongestion with acetazolamide in acute decompensated heart failure: the ADVOR trial. Eur Heart J. 2023;44(37):3672\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTestani JM, Chen J, McCauley BD, et al. Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation. 2010;122(3):265\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFelker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364(9):797\u0026ndash;805.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrisco-Bacik MA, Ter Maaten JM, Houser SR, et al. Outcomes Associated With a Strategy of Adjuvant Metolazone or High-Dose Loop Diuretics in Acute Decompensated Heart Failure: A Propensity Analysis. J Am Heart Assoc. 2018;7(18):e009149.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHanberg JS, Tang WHW, Wilson FP, et al. An exploratory analysis of the competing effects of aggressive decongestion and high-dose loop diuretic therapy in the DOSE trial. Int J Cardiol. 2017;241:277\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZornitzki L, Bornstein G. Potential role for furosemide in the treatment of acute respiratory distress syndrome (ARDS) and an unusual presentation of pulmonary embolism in a complex patient. BMJ Case Rep. 2020;13(8):e235010.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeitz KP, Caldwell ES, Hough CL. Fluid management in ARDS: an evaluation of current practice and the association between early diuretic use and hospital mortality. J Intensive Care. 2020;8:78.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGabarre P, Desnos C, Morin A, et al. Albumin versus saline infusion for sepsis-related peripheral tissue hypoperfusion: a proof-of-concept prospective study. Crit Care. 2024;28(1):43.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Sepsis, Mechanical ventilation, Albumin, Loop diuretics, Propensity score matching","lastPublishedDoi":"10.21203/rs.3.rs-8607908/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8607908/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003eFluid overload and hypoalbuminemia are typical and associated with poor outcomes in patients with sepsis receiving mechanical ventilation. While loop diuretics are used for fluid management, their efficacy can be limited by intravascular volume depletion and hypoalbuminemia. This study examines whether the combined administration of albumin and loop diuretics enhances clinical outcomes in this high-risk population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e In this retrospective cohort study utilizing the MIMIC-IV database, adult patients with sepsis who required mechanical ventilation were categorized into two groups: those receiving albumin alone and those receiving albumin in combination with loop diuretics. Propensity score matching was employed to ensure balance in baseline characteristics between the groups. The primary outcome of the study was in-hospital mortality, while secondary outcomes included mortality rates at 30 and 90 days, length of hospital stay, and fluid balance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e After matching, a total of 1,032 patients were included in each group. The in-hospital mortality rate was significantly lower in the combination therapy group compared to the albumin-alone group (21.2% vs. 33.0%, p \u0026lt; 0.001). Similarly, the 30-day (22.4% vs. 32.8%) and 90-day (28.3% vs. 40.0%) mortality rates were also reduced, with both differences being statistically significant (p \u0026lt; 0.001). The combination therapy group exhibited a significantly lower 7-day fluid balance (1,462 mL vs. 4,304 mL, p \u0026lt; 0.001), despite longer durations of ICU and hospital stays. Subgroup analyses indicated a consistent benefit across most subgroups. A dose-response relationship was observed, with low-to-moderate furosemide-equivalent doses (\u0026lt;40 mg/day) associated with reduced mortality (HR 0.37–0.58). In contrast, higher doses (\u0026gt;80 mg/day) did not demonstrate any survival advantage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eIn patients with sepsis receiving mechanical ventilation, the combination of albumin and loop diuretics may be associated with reduced 30-day and 90-day mortality, as well as improved fluid balance compared to the use of albumin alone. The benefits appear to be dose-dependent, favoring low to moderate diuretic intensity. These findings suggest a potential therapeutic role for the combined use of albumin and loop diuretic therapy in this patient population.\u003c/p\u003e","manuscriptTitle":"Combination Therapy of Albumin and Loop Diuretics May Improve Survival in Patients with Sepsis Receiving Mechanical Ventilation: A Propensity Score Matched Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-11 16:46:28","doi":"10.21203/rs.3.rs-8607908/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-02-06T14:10:34+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-19T19:03:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-19T16:03:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-19T16:01:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2026-01-15T07:19:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ac2fe51b-485f-4727-aa35-ef062d506839","owner":[],"postedDate":"February 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-11T16:46:28+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-11 16:46:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8607908","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8607908","identity":"rs-8607908","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}