Introduction
In the international consensus definition issued by the World Society of the Abdominal Compartment Syndrome (WSACS) in 2006, intra-abdominal hypertension (IAH) is defined as a persistent or recurrent pathological elevation of intra-abdominal pressure (IAP) (≥ 12 mmHg) [1]. As a common complication in critically ill patients, the incidence of IAH varies among different patient populations, ranging from 40 to 60% [2–5]. The development of IAH often results in impaired systemic perfusion and multiple organ dysfunction syndrome (MODS), such as acute kidney injury (AKI) and pulmonary edema.
These complications not only pose substantial clinical challenges but also significantly increase the risk of mortality in affected patients [6–10].
Currently, there remains a lack of adjuvant therapeutic drugs that can clearly improve survival in patients with IAH. Treatment primarily focuses on reducing IAP to restore systemic perfusion and prevent organ damage [11]. Recommended strategies include improving abdominal wall compliance, evacuating intra-abdominal contents, correcting positive fluid balance, and supporting organ function [12].
Among these strategies, correcting volume overload is particularly crucial for patients with IAH. Excessive fluid accumulation can further elevate IAP and exacerbate multiple organ injury. Therefore, diuretics, especially furosemide, have garnered increasing clinical attention due to their potential to break this vicious cycle [13–15].
Specifically, furosemide has been demonstrated to improve short-term survival and renal function recovery in patients with AKI—a common complication in IAH patients due to inadequate renal perfusion caused by elevated iap. Additionally, combination therapy with furosemide and albumin has been associated with a reduction in in-hospital mortality in septic patients with hypoalbuminemia [9, 16, 17]. For patients with IAH who frequently present with concurrent volume overload, these findings suggest that furosemide may target key pathophysiological pathways in their management, while its specific efficacy in this population remains to be further investigated.
Despite the WSACS suggesting potential value for diuretics in IAH treatment, evidence regarding their impact on mortality risk is inconclusive [12]. Furosemide, by reducing fluid load, may exert a beneficial effect on clinical prognosis in IAH patients. Therefore, we conducted a retrospective propensity score-matched cohort study using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database to examine the relationship between furosemide use and all-cause mortality in critically ill IAH patients.
Methods
Data source
This study performed a retrospective analysis utilizing data from the MIMIC-IV 3.1 database. MIMIC-IV is an open–access dataset containing comprehensive medical records of patients admitted to the intensive care units at Beth Israel Deaconess Medical Center, Boston, between 2008 and 2019. Curated by the Laboratory for Computational Physiology at MIT, the dataset includes demographic, clinical, laboratory, and outcome data.
The author of this study successfully finished the training program provided by the partnering institution, passed exams on topics such as 'conflict of interest' and 'research utilizing only data or samples,' and was granted permission to access the MIMIC-IV database [18]. The study was conducted in compliance with the database usage agreement (certification number: 62302397).
Study population
All consecutive patients were considered for inclusion in this study. The inclusion criteria were as follows: (1) Patients with IAH were defined as those with iap that is persistently or recurrently elevated to ≥ 12 mmHg [12]; (2) Aged 18 years or older; (3) For patients with multiple intensive care unit (ICU) admission records, only data from the first admission were evaluated. Patients with an ICU stay of less than 24 h were excluded from the study.
Medication exposure and clinical outcomes
The exposure factor was the use of furosemide during ICU hospitalization, with no restrictions on its administration. Data on furosemide usage were extracted from the mimiciv_icu.inputevents table of the MIMIC-IV database, and the drug dosage form was confirmed by linking to the d_items table via itemid. There are two furosemide-related itemids in mimiciv_icu: 221,794 and 228,340 (furosemide 250 mg/50 mL, high-concentration formulation).
To focus on the efficacy analysis of conventional doses, only records with itemid 221,794 were included in this study. The primary outcome was 28-day all-cause mortality. Secondary outcomes included 7-day, 90-day, and 180-day all-cause mortality.
To evaluate the impact of furosemide use on clinical outcomes, eligible patients were assigned to either the furosemide group or the non-furosemide group based on whether they received furosemide treatment during their ICU hospitalization.
Data extraction
All data were extracted from the MIMIC-IV database using Structured Query Language (SQL). The following data were collected: Demographic characteristics, including age, gender, race, and weight;
Vital signs, including body temperature, heart rate (HR), respiratory rate (RR), and abdominal perfusion pressure (APP); Comorbidities, including renal failure (RF), heart failure (HF), hypertension, diabetes, sepsis, and pancreatitis; Severity scores, including Simplified Acute Physiology Score Ⅱ (SAPS Ⅱ) and Sequential Organ Failure Assessment (SOFA); patients with IAH were further stratified into grades Ⅰ-Ⅳ based on the maximum IAP recorded during ICU stay [12]; Laboratory parameters, including hemoglobin, platelets, white blood cell (WBC) count, blood urea nitrogen (BUN), calcium, chloride, creatinine, glucose, sodium, potassium, prothrombin time (PT), alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin, creatine kinase-MB (CK-MB), lactate, pH, and red blood cell (RBC) count; Clinical interventions, including renal replacement therapy (RRT), mechanical ventilation (MV), vasoactive agents, and nerve block drugs administered during ICU hospitalization. Variables with more than 10% missing values were excluded from the analysis. Body weight, with 0.2% missing values, was imputed using the mean value; other variables with less than 10% missing values were handled using multiple imputation.
The missing rate of each variable is presented in the supplementary material (Figure S1: Variable missing values distribution). The following variables were excluded due to missing values exceeding 10%: ALT, AST, total bilirubin, CK-MB, lactate, and pH.
Statistical analysis
The normality of the data was assessed using the Kolmogorov–Smirnov test. For normally distributed data, continuous variables are presented as mean ± standard deviation (x̄ ± s) and compared between groups using the independent–samples t–test. For non–normally distributed data, continuous variables are presented as median (interquartile range, IQR) [Md (P25, P75)], and group comparisons were performed using the Mann–Whitney U test.
Categorical variables are presented as frequencies (n, %) and compared between groups using Pearson’s χ2 test.
For primary and secondary outcomes, Cox univariate regression analysis was used to screen baseline variables. Variables with a P-value < 0.05 in univariate analysis, along with other clinically relevant variables based on prior knowledge, were included in the Cox multivariate regression model. Corresponding hazard ratios (HR) and 95% confidence intervals (CI) were reported.
The cumulative incidence of all-cause mortality at 7, 28, 90, and 180 days was estimated using the Kaplan–Meier (K-M) survival curves, with between-group comparisons performed via the log-rank test.Multicollinearity among covariates included in PSM was assessed using the variance inflation factor (VIF). A VIF < 5 was considered indicative of no significant multicollinearity (Table S1).
Additional exploratory analyses were performed to assess the consistency of the association across clinically relevant subgroups. Furosemide dose was dichotomized into low-dose and high-dose categories using the median cumulative ICU dose as the cutoff. Administration method was also examined by comparing intermittent versus continuous infusion.
Data analysis was performed using SPSS version 26.0 and R version 4.3.2. A significance level of α = 0.05 was used for all statistical tests.
Propensity score matching
To address potential confounding factors and selection bias in observational studies, we employed propensity score matching (PSM) to balance baseline covariates and ensure the reliability of the study results [19]. A 1:1 nearest-neighbor matching method was used, with a caliper width of 0.05. The covariates included in the propensity score model were selected based on the following criteria: 1) variables with a p-value < 0.05 in univariate analysis; 2) variables identified from published consensus statements, including Age, Weight, Body temperature, RR, APP, Creatinine, Chloride, PT, BUN, WBC, RBC, Sodium, Platelets, Hemoglobin, Potassium, Calcium, SOFA, SAPS II, Sepsis, RF, HF, Grade, MV, RRT, Vasoactive agent, Nerve block drugs.
Subgroup analysis
To evaluate the impact of different variables on 28-day all-cause mortality in patients with IAH, we performed a subgroup analysis stratified by age, gender, race, baseline severity scores (SOFA and SAPS II scores), chronic comorbidities (hypertension, diabetes, sepsis, pancreatitis), baseline treatments (RRT, MV, vasoactive agents, and nerve block drugs), APP, and WSACS classification.
Results
Patient selection
A total of 1,944 patients who underwent bladder pressure measurement in the ICU were identified in the database. After excluding patients with multiple admissions, those with only one pressure measurement, suspected cases (defined as a single measurement ≥ 12 mmHg), and patients without confirmed diagnosis, a total of 859 patients were included, consisting of 534 (62.17%) in the furosemide group and 325 (37.83%) in the non-furosemide group. The patient selection process is shown in Fig.
1.Fig. 1Flow chart diagram of the study. Abbreviations: MIMIC-IV, Medical Information Mart in Intensive Care-IV; IAH, intra-abdominal hypertension; PSM, Propensity Score Matching
Baseline characteristics of patients with IAH
In the original cohort, compared with the non-furosemide group, the furosemide group had significantly higher APP, lower SOFA and SAPS II scores, a higher proportion of patients with IAH grades III and IV, a higher incidence of sepsis, lower RRT use, but higher utilization rates of MV, vasoactive agents, and nerve block drugs (detailed information in Table 1). After PSM, 506 patients (253 in each group) were included for further analysis, with most baseline characteristic biases corrected (Supplementary Figure S2 and Figure S3).Table 1Baseline characteristics of IAHVariableBefore PSMAfter PSMTotal (n = 859)0 (n = 325)1 (n = 534)PSMDTotal (n = 506)0 (n = 253)1 (n = 253)PSMDDemographicAge, (years)60.00 (50.00, 70.00)59.00 (50.00, 69.00)61.00 (50.00, 72.00)0.2170.07360.00 (50.25, 69.00)60.00 (51.00, 69.00)59.00 (50.00, 69.00)0.729-0.036Weight, (kg)87.50 (74.00, 104.55)86.35 (72.30, 102.00)88.65 (74.93, 105.11)0.2830.00187.50 (73.49, 105.26)86.70 (72.00, 104.30)89.00 (75.45, 106.00)0.1820.027Gender, n (%)0.7941.000Female306 (35.62)114 (35.08)192 (35.96)0.018170 (33.6)85 (33.60)85 (33.60)0.000Male553 (64.38)211 (64.92)342 (64.04)-0.018336 (66.4)168 (66.40)168 (66.40)0.000Race, n (%)0.5990.680Black72 (8.38)30 (9.23)42 (7.87)-0.05142 (8.3)21 (8.30)21 (8.30)0.000Other266 (30.97)95 (29.23)171 (32.02)0.060161 (31.82)76 (30.04)85 (33.60)0.075White521 (60.65)200 (61.54)321 (60.11)-0.029303 (59.88)156 (61.66)147 (58.10)-0.072Vital signsHR, (beats/min)118.00 (102.00, 133.00)118.00 (103.00, 130.00)118.00 (102.00, 134.00)0.6180.036119.00 (103.00, 132.75)118.00 (103.00, 131.00)119.00 (103.00, 135.00)0.4150.068RR, (beats/min)30.00 (25.00, 34.00)30.00 (26.00, 35.00)29.00 (25.00, 34.00)0.129-0.08230.00 (26.00, 35.00)30.00 (25.00, 34.00)30.00 (26.00, 35.00)0.2590.106Body temperature, (°C)37.56 (37.10, 38.17)37.40 (37.00, 38.00)37.67 (37.11, 38.28)0.0020.17537.50 (37.11, 38.11)37.50 (37.11, 38.10)37.56 (37.06, 38.22)0.5500.022APP, (mmHg)81.67 (70.67, 95.00)78.33 (68.33, 91.00)84.00 (73.00, 97.33) < .0010.31879.33 (70.00, 91.92)78.67 (70.00, 91.67)80.00 (70.33, 92.33)0.5380.033BiochemistryHemoglobin, (g/dL)11.30 (10.00, 13.10)11.20 (9.80, 12.90)11.55 (10.10, 13.20)0.0930.09311.25 (10.00, 13.10)11.30 (10.00, 13.20)11.20 (10.00, 13.10)0.914-0.016Platelets, (103/μL)192.00 (123.00, 273.00)175.00 (107.00, 272.00)200.00 (132.25, 273.75)0.0080.131180.50 (115.00, 269.00)177.00 (111.00, 273.00)183.00 (120.00, 266.00)0.7010.000WBC count, (103/μL)15.10 (10.30, 21.85)15.70 (10.80, 22.90)14.70 (10.20, 20.88)0.073-0.18615.10 (10.30, 22.30)14.60 (9.80, 22.10)15.40 (10.60, 22.50)0.6750.052BUN, (mg/dL)29.00 (19.00, 48.00)31.00 (21.00, 52.00)27.00 (18.00, 44.00)0.002-0.22331.00 (20.25, 51.00)29.00 (20.00, 51.00)32.00 (21.00, 48.00)0.639-0.002Calcium, (mg/dL)8.30 (7.80, 8.90)8.40 (7.80, 9.10)8.30 (7.80, 8.90)0.157-0.0528.30 (7.80, 8.90)8.40 (7.80, 8.90)8.30 (7.70, 8.90)0.307-0.064Chloride, (mEq/L)107.00 (102.00, 111.00)106.00 (101.00, 110.00)107.00 (103.00, 112.00) < .0010.332106.00 (102.00, 111.00)107.00 (101.00, 111.00)106.00 (102.00, 111.00)0.7520.049Creatinine, (mg/dL)1.80 (1.10, 2.90)2.10 (1.30, 3.40)1.60 (1.02, 2.60) < .001-0.6232.00 (1.20, 3.08)2.00 (1.30, 3.00)2.00 (1.20, 3.10)0.806-0.040Glucose, (mg/dL)170.00 (130.00, 225.00)168.00 (128.00, 236.00)172.00 (133.25, 221.00)0.958-0.100166.50 (129.00, 221.00)167.00 (128.00, 227.00)166.00 (133.00, 218.00)0.716-0.056Sodium, (mEq/L)140.00 (136.00, 143.00)140.00 (136.00, 143.00)140.00 (137.00, 143.00)0.1040.145140.00 (136.00, 142.75)140.00 (136.00, 143.00)140.00 (136.00, 142.00)0.7330.025Potassium, (mEq/L)4.80 (4.30, 5.40)4.80 (4.30, 5.50)4.70 (4.30, 5.40)0.162-0.0794.70 (4.30, 5.40)4.80 (4.20, 5.40)4.70 (4.30, 5.40)0.924-0.009PT, (s)18.00 (14.60, 24.55)19.70 (15.00, 27.50)17.00 (14.20, 22.40) < .001-0.28218.85 (14.80, 25.28)19.00 (14.80, 26.00)18.40 (14.80, 25.20)0.654-0.019RBC, (m/uL)4.30 (3.70, 4.87)4.25 (3.59, 4.75)4.31 (3.75, 4.91)0.1190.1004.28 (3.62, 4.85)4.32 (3.64, 4.84)4.22 (3.61, 4.87)0.730-0.044Clinical scoreSOFA9.00 (6.00, 13.00)10.00 (6.00, 14.00)9.00 (6.00, 12.00) < .001-0.31710.00 (6.25, 14.00)10.00 (6.00, 14.00)10.00 (7.00, 13.00)0.8610.009SAPS II49.00 (37.50, 60.00)52.00 (39.00, 62.00)48.00 (37.00, 58.00)0.002-0.25750.00 (38.25, 61.00)51.00 (38.00, 61.00)50.00 (39.00, 60.00)0.841-0.046Grade, n (%)0.0090.859176 (8.85)20 (6.15)56 (10.49)0.14132 (6.32)16 (6.32)16 (6.32)0.0002294 (34.23)101 (31.08)193 (36.14)0.105165 (32.61)80 (31.62)85 (33.60)0.0423237 (27.59)90 (27.69)147 (27.53)-0.004146 (28.85)71 (28.06)75 (29.64)0.0354252 (29.34)114 (35.08)138 (25.84)-0.211163 (32.21)86 (33.99)77 (30.43)-0.077ComorbidityRF, n (%)0.1680.8530316 (36.79)129 (39.69)187 (35.02)-0.098180 (35.57)89 (35.18)91 (35.97)0.0161543 (63.21)196 (60.31)347 (64.98)0.098326 (64.43)164 (64.82)162 (64.03)-0.016HF, n (%)0.2710.4550714 (83.12)276 (84.92)438 (82.02)-0.076430 (84.98)212 (83.79)218 (86.17)0.0691145 (16.88)49 (15.08)96 (17.98)0.07676 (15.02)41 (16.21)35 (13.83)-0.069Hypertension, n (%)0.6710.4230407 (47.38)157 (48.31)250 (46.82)-0.030243 (48.02)117 (46.25)126 (49.80)0.0711452 (52.62)168 (51.69)284 (53.18)0.030263 (51.98)136 (53.75)127 (50.20)-0.071Diabetes, n (%)0.6491.0000613 (71.36)229 (70.46)384 (71.91)0.032356 (70.36)178 (70.36)178 (70.36)0.0001246 (28.64)96 (29.54)150 (28.09)-0.032150 (29.64)75 (29.64)75 (29.64)0.000Sepsis, n (%) < .0010.482088 (10.24)52 (16.00)36 (6.74)-0.36957 (11.26)31 (12.25)26 (10.28)-0.0651771 (89.76)273 (84.00)498 (93.26)0.369449 (88.74)222 (87.75)227 (89.72)0.065Pancreatitis, n (%)0.8160.1570705 (82.07)268 (82.46)437 (81.84)-0.016399 (78.85)206 (81.42)193 (76.28)-0.1211154 (17.93)57 (17.54)97 (18.16)0.016107 (21.15)47 (18.58)60 (23.72)0.121MedicationRRT, n (%) < .0010.7190566 (65.89)176 (54.15)390 (73.03)0.425294 (58.1)149 (58.89)145 (57.31)-0.0321293 (34.11)149 (45.85)144 (26.97)-0.425212 (41.9)104 (41.11)108 (42.69)0.032MV, n (%) < .0010.888086 (10.01)55 (16.92)31 (5.81)-0.47557 (11.26)28 (11.07)29 (11.46)0.0121773 (89.99)270 (83.08)503 (94.19)0.475449 (88.74)225 (88.93)224 (88.54)-0.012MedicationVasoactive agent, n (%)0.0021.0000229 (26.66)106 (32.62)123 (23.03)-0.228140 (27.67)70 (27.67)70 (27.67)0.0001630 (73.34)219 (67.38)411 (76.97)0.228366 (72.33)183 (72.33)183 (72.33)0.000Nerve block drugs, n (%)0.0090.7500653 (76.02)263 (80.92)390 (73.03)-0.178391 (77.27)197 (77.87)194 (76.68)-0.0281206 (23.98)62 (19.08)144 (26.97)0.178115 (22.73)56 (22.13)59 (23.32)0.028Abbreviations: IAH Intra-abdominal hypertension, HR Heart rate, RR Respiratory rate, APP Abdominal perfusion pressure, WBC White blood cell, BUN Blood urea nitrogen, PT Prothrombin time, RBC Red blood cell, SOFA Sequential Organ Failure Assessment, SAPS Ⅱ Simplified Acute Physiology Score Ⅱ, RF Renal failure, HF Heart failure, RRT Renal replacement therapy, MV Mechanical ventilation
Outcomes of patients with IAH
In the original cohort, the furosemide group exhibited significantly lower 7-day, 28-day, 90-day, and 180-day all-cause mortality rates compared with the non-furosemide group (Supplementary Table S2, Supplementary Figure S4). After PSM, the furosemide group continued to exhibit significantly lower mortality at 7 days (6.7% vs. 27.3%, P < 0.001), 28 days (25.3% vs.
47.8%, P < 0.001), 90 days (30.0% vs. 50.6%, P < 0.001), and 180 days (30.8% vs. 50.6%, P < 0.001) (Table 2, Fig.
2).Table 2Clinical outcomes of IAH after PSMNon-furosemide groupFurosemide groupP value7-day mortality69 (27.3%)17 (6.7%) < 0.00128-day mortality121 (47.8%)64 (25.3%) < 0.00190-day mortality128 (50.6%)76 (30.0%) < 0.001180-day mortality128 (50.6%)78 (30.8%) < 0.001Abbreviations: IAH Intra-abdominal hypertension, PSM Propensity score matchingFig. 2Kaplan–Meier Curves after PSM. A 7-day mortality; B 28-day mortality; C 90-day mortality; D 180-day mortality.
Abbreviations: PSM, propensity score matching
Survival analysis and cox regression modeling
In the PSM-matched cohort, multivariable models (Model 1, Model 2, and the fully adjusted Model 3) consistently demonstrated that furosemide administration was an independent protective factor for all-cause mortality among patients with IAH. Specifically, in the fully adjusted Model 3, furosemide use was associated with significantly reduced mortality risks at multiple time points: 7-day (HR = 0.19, 95%CI 0.11–0.34, P < 0.001), 28-day (HR = 0.35, 95%CI 0.26–0.48, P < 0.001), 90-day (HR = 0.39, 95%CI 0.29–0.52, P < 0.001), and 180-day (HR = 0.40, 95%CI 0.30–0.54, P < 0.001) (Supplementary Table S3, Table 3). Similar findings were observed in multivariable Cox regression analyses of the original cohort, where all three models (Model 1, Model 2, and Model 3) demonstrated the significant mortality benefit of furosemide treatment in patients with IAH (Supplementary Table S4).Table 3Results of cox multivariate analysis after PSMMortalityModelHR (95% CI)P value7-day mortalityModel 10.22 (0.13–0.37) < 0.001Model 20.20 (0.12–0.35) < 0.001Model 30.19 (0.11–0.34) < 0.00128-day mortalityModel 10.42 (0.31–0.57) < 0.001Model 20.39 (0.29–0.54) < 0.001Model 30.35 (0.26–0.48) < 0.00190-day mortalityModel 10.47 (0.35–0.62) < 0.001Model 20.44 (0.33–0.58) < 0.001Model 30.39 (0.29–0.52) < 0.001180-day mortalityModel 10.48 (0.36–0.64) < 0.001Model 20.45 (0.34–0.60) < 0.001Model 30.40 (0.30–0.54) < 0.001Model 1: NoneModel 2: Adjust: Gender, Race, Age, WeightModel 3: Adjust: Gender, Race, Age, Weight, Renal failure, Heart failure, Sepsis, Pancreatitis, Renal replacement therapy, Mechanical ventilation, Vasoactive agent, Nerve block drugs, Intra-abdominal hypertension grade, Body temperature, Platelets, White blood cell count, Blood urea nitrogen, Calcium, Chloride, Creatinine, Potassium, Prothrombin time, Red blood cell count, SOFA score, SAPSII score, Abdominal perfusion pressureAbbreviations: PSM Propensity score matching
In supplementary analyses, similar associations were observed when stratifying by furosemide dose (low vs high) and by administration method (intermittent vs continuous), as detailed in Supplementary Tables S5.
Subgroup analysis
Subgroup analyses were performed based on age, gender, race, baseline severity scores (SOFA and SAPS II), chronic comorbidities (hypertension, diabetes, sepsis, acute pancreatitis), baseline treatments (RRT, MV, vasoactive agents, and nerve blockers), intra-abdominal pressure, and WSACS classification. Specifically, focusing on etiologies and interventions pertinent to IAH, the most notable benefits were seen in subgroups of sepsis (HR = 0.42, 95% CI 0.30–0.57, P < 0.001), MV use (HR = 0.42, 95% CI 0.30–0.57, P < 0.001), and RRT use (HR = 0.49, 95% CI 0.33–0.74, P < 0.001).
Figure 3 presented the results of subgroup analysis for 28-day all-cause mortality in the matched cohort. A significant interaction was observed between sex and furosemide efficacy (P for interaction = 0.009). Although subgroups such as Black race, abnormal APP, and vasoactive agent use showed wider 95% confidence intervals that included 1.00, indicating less precision, furosemide consistently demonstrated a reduction in mortality risk across the majority of subgroups.Fig.
3Subgroup analysis of the patients with IAH. Abbreviations: SOFA, Sequential Organ Failure Assessment; SAPS Ⅱ, Simplified Acute Physiology Score Ⅱ; APP, abdominal perfusion pressure; RRT, renal replacement therapy; MV, mechanical ventilation
Discussion
In this propensity score–matched retrospective cohort study including 859 patients with intra-abdominal hypertension, we evaluated the association between furosemide use and clinical outcomes in a large real-world ICU setting. Furosemide use was independently associated with lower 7-day, 28-day, 90-day, and 180-day all-cause mortality, indicating a potentially beneficial association that warrants confirmation in future prospective studies.
The survival benefit of furosemide observed in patients with IAH is highly consistent with the physiological principles underlying IAH treatment. It is currently well-recognized that reducing IAP constitutes the core strategy to alleviate organ hypoperfusion and subsequent failure [11, 20]. By promoting diuresis and reducing intravascular volume, furosemide may help alleviate volume overload associated with abdominal compartment syndrome, thereby lowering IAP, preserving organ function, and improving the prognosis of patients with IAH.
Indeed, furosemide has also demonstrated the potential to improve prognosis in other critical care scenarios, with its mechanisms not limited to regulating fluid balance but also encompassing multiple aspects such as organ function protection [21–23]. A study based on the MIMIC-III database found that furosemide could reduce in-hospital mortality and 90-day mortality in critically ill patients with AKI, as well as promote renal function recovery [16]. This study suggests that furosemide may exert protective effects through mechanisms such as improving renal hemodynamics and alleviating renal interstitial edema, which is consistent with the mechanism of improving intra-abdominal organ perfusion in IAH.
In addition, another study based on the MIMIC-IV database explored the effect of combined administration of albumin and loop diuretics in septic patients with hypoalbuminemia [17]. The results showed that combined treatment significantly reduced in-hospital mortality, and the timing of diuretic administration, particularly after albumin infusion, was associated with a further reduction in mortality.
The pleiotropic effects of furosemide have been fully documented in the literature. However, the underlying mechanisms responsible for its beneficial effects in patients with IAH remain unclear. One plausible explanation is that the gastrointestinal tract serves as a trigger for multiple organ dysfunction syndrome in critically ill patients, and its pathophysiological changes are closely linked to IAH [24].
Animal studies have shown that elevated IAP inhibits intestinal blood perfusion, leading to intestinal mucosal ischemia-hypoxia, barrier function impairment, and infection. These changes, in turn, trigger the entry of bacteria and endotoxins into the bloodstream, forming a vicious cycle [25, 26]. Meanwhile, elevated IAP significantly affects renal function, resulting in inadequate renal perfusion, decreased glomerular filtration rate, and damage to renal tubular epithelial cells [27–29].
Furosemide exerts its effects by binding to albumin and being secreted into the tubular lumen via organic anion transporters. It then inhibits the Na–K-Cl cotransporter (NKCC2), preventing sodium reabsorption in the thick ascending limb of the loop of Henle. This also reduces the transport of calcium and magnesium [30].
This process increases urinary sodium excretion and decreases intravascular volume. Consequently, it alleviates elevated IAP, maintains intestinal barrier function, reduces bacterial translocation, and mitigates the impact of diaphragmatic elevation on respiratory function. Ultimately, furosemide exerts its effects through a cascade of events involving "tubular sodium blockade—volume reduction—IAP decrease—improvement of multi-organ perfusion".
Subgroup analysis of the matched cohort, stratified by IAH grades based on the WSACS criteria, showed that furosemide had a statistically significant protective effect in patients with grade II (HR = 0.42; 95% CI = 0.24–0.73; p = 0.002), grade III (HR = 0.38; 95% CI = 0.22–0.66; p < 0.001), and grade IV (HR = 0.48; 95% CI = 0.29–0.81; p = 0.006) IAH. Although the hazard ratio in grade I patients (HR = 0.40; 95% CI = 0.12–1.34; p = 0.139) exhibited a similar trend, it failed to reach statistical significance. From a statistical standpoint, this result is probably due to insufficient power caused by the limited sample size (n = 32, 6.32%), which made it difficult to detect the true effect difference.
In terms of the pathophysiology of the disease, the clinical significance of grade I IAH (IAP 12–15 mmHg) is controversial. The traditional view holds that this stage is a "subclinical period" with mild impacts on organ function, and some studies even propose that active intervention is not required [31–33]. However, recent experimental studies have confirmed that subclinical organ damage may already occur insidiously within the IAP range of 10–15 mmHg, but its clinical manifestations and prognostic effects have not yet reached a clinically recognizable significant level [34–36].
As IAP increases, the progressive decrease in organ perfusion pressure will lead to the overt manifestation of dysfunction, which also explains why the protective effect of furosemide is more significant in patients with grades II-IV IAH [37]. In contrast, the potential damage in grade I patients has not yet accumulated to the "threshold" requiring drug intervention, so the clinical manifestation of therapeutic benefits is relatively low. The negative result in the grade I IAH subgroup is more likely the combined effect of limited sample size and weak early intervention effect of the disease, rather than true biological ineffectiveness.
In addition to efficacy differences associated with IAH grades, subgroup analyses of this study identified sex and age as important factors influencing the therapeutic effects of furosemide. Regarding sex differences, the reduction in mortality risk with furosemide was significantly greater in female patients than in male patients (female HR = 0.22 vs. male HR = 0.55). This sex discrepancy may be related to the expression level of renal Na–K-2Cl cotransporter, a key target of furosemide.
Animal studies have shown that the abundance of this transporter in the renal medulla is lower in females than in males, resulting in more pronounced natriuretic and diuretic responses to furosemide in females and thus a more significant reduction in mortality risk [38]. Age-related differences are closely linked to organ reserve function: younger patients may derive greater benefits due to better organ reserve, enabling more effective diuresis and reduction of IAP. In contrast, elderly patients are often accompanied by comorbidities, which can weaken the diuretic effect and increase the risk of adverse events—potentially explaining the attenuated efficacy [39, 40].
Clinically, this suggests that furosemide may be more effective in younger patients with IAH, while elderly patients require careful dosage adjustment and renal function monitoring. It should be acknowledged that the subgroup analyses in this study are exploratory, and sample size limitations may affect the stability of some conclusions.
The main strength of this study lies in the adoption of the PSM method. By balancing the baseline characteristics between patients in the furosemide—using group and the non—using group, this method successfully controlled for potential confounding biases, thereby providing an unbiased doubly robust estimation of the therapeutic effect of furosemide in IAH patients and enhancing the reliability of the study results. However, the study also has some limitations.
Firstly, as an observational retrospective study, causal inference is inherently limited, and the possibility of residual or unmeasured confounding cannot be completely ruled out despite extensive adjustment and propensity score matching. Secondly, this study establishes an association rather than a definitive causal relationship between furosemide use and mortality, and prospective studies are warranted to further validate these findings. Thirdly, although subgroup analyses suggested potential benefits across different IAH grades, the optimal timing, patient selection criteria, and administration strategy for furosemide were not determined.
Finally, several variables related to IAP and furosemide exposure were limited by the structure of the database, underscoring the need for prospective studies with precise time-resolved measurements.
Conclusion
This retrospective study demonstrates that furosemide use is associated with reduced 7-day, 28-day, 90-day, and 180-day all-cause mortality in ICU patients with IAH. These findings highlight the potential clinical value of furosemide in the management of IAH, but prospective randomized controlled trials are warranted to validate these results and determine the optimal dosage and administration timing of furosemide in this patient population.
Supplementary Information
Supplementary Material 1