Diuretic therapy for critically ill patients: a systematic review and network meta-analysis

Akira Kuriyama; Kamil Polok; Nikita Malhotra; Naoyuki Kuse; Tyler Pitre; Devan Lakhanpal; Rao Sun; Kapil Dev Soni; Kaitryn Campbell; Lisa D Burry; Edward G Clark; Kimberley Lewis; Morten Hylander Møller; Hayley B Gershengorn; Bram Rochwerg

doi:10.1016/j.aicoj.2026.100120

. 2026 Jul 21;16:100120. doi: 10.1016/j.aicoj.2026.100120

Diuretic therapy for critically ill patients: a systematic review and network meta-analysis

Akira Kuriyama ^a,^⁎, Kamil Polok ^b, Nikita Malhotra ^c,^d, Naoyuki Kuse ^e, Tyler Pitre ^f, Devan Lakhanpal ^g, Rao Sun ^h, Kapil Dev Soni ⁱ, Kaitryn Campbell ^j, Lisa D Burry ^k,^l, Edward G Clark ^m,ⁿ, Kimberley Lewis ^a,^o, Morten Hylander Møller ^p,^q, Hayley B Gershengorn ^r,^s, Bram Rochwerg ^a,^o

^aDepartment of Health Research Methods, Evidence, and Impact, McMaster University, Ontario, Canada

^bCentre for Intensive Care and Perioperative Medicine, Jagiellonian University Medical College, Kraków, Poland

^cDepartment of Medicine, Division of Cardiology, McMaster University, Hamilton, ON, Canada

^dDepartment of Medicine, Division of Critical Care, McMaster University, Hamilton, ON, Canada

^eFirestone Institute for Respiratory Health at St. Joseph’s Healthcare, Hamilton, ON, Canada

^fUniversity Health Network, University of Toronto, Toronto, ON, Canada

^gDepartment of Chemical and Physical Sciences, University of Toronto, Toronto, ON, Canada

^hDepartment of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

ⁱCritical and Intensive Care, JPN Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi, India

^jCampbell Information Consulting, Inc., Petawawa, ON, Canada

^kDepartments of Pharmacy, Medicine, Sinai Health Research, Sinai Health, Toronto, ON, Canada

^lLeslie Dan Faculty of Pharmacy and Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON, Canada

^mDivision of Nephrology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada

ⁿKidney Research Centre, Ottawa Hospital Research Institute, Ottawa, ON, Canada

^oDepartment of Medicine, McMaster University, Hamilton, ON, Canada

^pDepartment Of Intensive Care, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

^qDepartment of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

^rDivision of Pulmonary, Critical Care, and Sleep Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America

^sDivision of Critical Care Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America

^⁎

Corresponding author. ak.bellyrub+015@gmail.com

PMCID: PMC13476641 PMID: 42604106

Abstract

Background

Fluid overload is common in critically ill patients and is associated with worse outcomes. Diuretics are the mainstay of active fluid removal in patients with preserved renal function. The optimal diuretic strategy for fluid removal remains uncertain.

Methods

We conducted a systematic review and Bayesian random-effects network meta-analysis of randomized controlled trials comparing two or more diuretic strategies for fluid removal in critically ill adults. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials via Ovid, as well as trial registries, from inception to November 20, 2025. Two reviewers independently extracted data and assessed risk of bias using ROBUST-RCT. Certainty of evidence was evaluated using the GRADE approach for network meta-analysis. Treatment effects were summarized as odds ratios (ORs) or mean differences (MDs) with 95% credible intervals (CrIs).

Results

Twenty-six randomized controlled trials involving 1,652 participants were included. Evaluated interventions included bolus loop diuretics (19 studies), continuous loop infusion (15 studies), oral loop diuretics (5 studies), and loop diuretics combined with tolvaptan (8 studies), spironolactone (3 studies), thiazides (2 studies), acetazolamide (1 study), or triamterene (1 study). Compared with bolus loop diuretics, continuous loop infusion had an uncertain effect on mortality (OR 1.26; 95% CrI 0.62 to 2.55; very low certainty) and may increase ICU length of stay (MD 1.56 days; 95% CrI −0.02 to 3.16; low certainty). Tolvaptan monotherapy may reduce acute kidney injury compared with bolus or continuous loop diuretics (OR 0.12; 95% CrI 0.01 to 0.87; low certainty), although no studies evaluated its effect on the need for renal replacement therapy. For most other comparisons and outcomes, the certainty of evidence was low or very low.

Conclusions

Available evidence comparing diuretic strategies for fluid removal during ICU-level care is limited, clinically heterogeneous, and derived largely from heart failure and post-cardiovascular surgery populations. Bolus loop diuretics were at least comparable to alternate diuretic strategies for patient important outcomes in critically ill adults, but this was based mostly on low or very low certainty evidence. Tolvaptan monotherapy may decrease acute kidney injury, but its effect on subsequent need for RRT and mortality remains uncertain.

Keywords: Acute kidney injury, Critical illness, Diuretics, Network meta-analysis, Water-Electrolyte balance

Introduction

Fluid overload is common in critically ill patients. Patients with septic shock represent one important example of this broader intensive care unit (ICU) population; approximately 35% to–67% exhibit signs of fluid overload during their ICU stay [1,2]. It is associated with higher mortality [[3], [4], [5]], prolonged mechanical ventilation [6], longer ICU and hospital stays [7,8], and increased medical costs [7,8]. Timely fluid removal may mitigate these negative sequelae and improve outcomes.

Fluid removal strategies include diuretics for patients with preserved renal function and ultrafiltration for those not meeting urinary output goals. Loop diuretics are the mainstay in the ICU, but their effectiveness may be limited by reduced renal perfusion, hypoalbuminemia, and systemic inflammation, which are common in critically ill patients [[9], [10], [11]]. Sequential nephron blockade, combining loop diuretics with drugs targeting more distal nephron segments (e.g., hydrochlorothiazide or metolazone), is used widely in heart failure [12]. However, its applicability in critically ill patients remains uncertain.

The European Society of Intensive Care Medicine (ESICM) recently issued a conditional recommendation favoring protocolized fluid removal using diuretics over usual care in critically ill patients, specifically following acute fluid resuscitation [13]. However, fluid removal could occur in diverse ICU populations across all phases of critical illness, while optimal diuretic strategies in general critically ill patients remain uncertain. We therefore conducted a systematic review and network meta-analysis (NMA) to examine the efficacy and safety of various diuretic strategies for fluid removal in critically ill adults.

Methods

We registered this review protocol on PROSPERO (CRD420251012660) on March 17, 2025, and followed the PRISMA-NMA statement for reporting this review [14].

Eligibility criteria

We included randomized controlled trials (RCTs) comparing two or more diuretic strategies from different pharmacological classes in critically ill adults, including monotherapy or combinations, regardless of administration route or treatment duration. Because our primary interest was the comparative effect of diuretic strategies, interventions were classified according to drug class and administration strategy rather than dose. Diuretics were eligible only when used specifically for fluid removal. Studies using diuretics for other purposes (such as the treatment or prevention of acute kidney injury [AKI], correction of hyponatremia, or management of cerebral edema) were excluded. The timing of diuretic initiation relative to ICU admission could not be consistently determined; however, the included studies evaluated diuretic therapy administered or continued during ICU-level care. We excluded sodium–glucose cotransporter 2 inhibitors and comparisons within the same pharmacological class (e.g., furosemide vs ethacrynic acid). Given that our interest was the comparison between diuretic regimens, we excluded studies comparing diuretics versus no diuretics, placebo, or usual care. Conference abstracts were included if sufficient outcome data were available.

Eligible studies enrolled adults, defined by the original studies, admitted to a critical care unit regardless of illness etiology, requiring fluid removal either following acute resuscitation or due to de novo fluid overload. We defined a critical care unit as ICUs, high-dependency units, or cardiac care units, representing higher-level care than general wards. Studies were included if at least 50% of patients met this definition when location was partially reported. Studies were excluded if treatment location could not be determined.

Information sources and search strategy

We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials via Ovid without restrictions on language or publication status and updated the search on November 20, 2025. We screened reference lists of eligible studies, relevant systematic reviews, and Google Scholar to identify additional studies as well as ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. The librarian-assisted search strategy is presented in eTable S1.

Study selection

Pairs of reviewers (from among authors AK, KP, NM, NK, DL, KDS, RS) independently and in duplicate screened titles and abstracts using Covidence (Melbourne, Australia). Citations deemed potentially relevant by either reviewer were advanced to full-text review. Two reviewers then independently and in duplicate screened full texts of retrieved studies. Disagreements were resolved by consensus. Although the PROSPERO registration did not allow sufficient detail regarding the use of AI, we did not use AI for any part of this review, as originally planned.

Data collection process and items

Two paired reviewers (from among authors AK, KP, NK, RS) extracted data independently and in duplicate using a standardized Microsoft Excel form, including study characteristics, participant demographics, interventions, comparators, and outcomes. Discrepancies were resolved by discussion.

Outcomes

Outcomes collected included mortality (longest reported up to 90 days), duration of invasive mechanical ventilation (IMV), AKI (per study definitions), requirement of renal replacement therapy (RRT), ICU and hospital length of stay, urine output and fluid balance at the longest reported time point, and adverse events (hypokalemia and arrhythmia).

Risk of bias

Two reviewers (from among authors AK, NK, KDS) independently, and in duplicate, assessed the risk of bias for each study using the Risk Of Bias instrument for Use in SysTematic reviews for Randomised Controlled Trials (ROBUST-RCT) at the outcome level [15]. ROBUST-RCT had not yet been published at the time of PROSPERO registration and was therefore not available as a selectable option; we therefore selected the closest available tool. We subsequently used ROBUST-RCT for risk of bias assessment, as originally planned. Disagreements were resolved through discussion. The overall risk of bias for each study was categorized as low, probably low, probably high, or high.

Certainty of evidence

We assessed the certainty of evidence using the GRADE approach [16,17]. We first rated all direct comparisons as in a conventional pairwise meta-analysis. The GRADE system classifies the certainty of evidence as high, moderate, low, or very low. Evidence from RCTs started as high certainty and was downgraded for risk of bias, indirectness, inconsistency, imprecision, or publication bias. We subsequently rated indirect comparisons, using the certainty from the most influential first-order loop (three treatments connected by direct comparisons) while considering intransitivity, considering the effect modifier distribution across comparisons.

We assessed for incoherence to identify important differences between direct and indirect estimates using node-splitting; when absent, we reported the network estimate and assigned a certainty to it based on the higher certainty of direct and indirect estimates and when present, we reported the direct or indirect estimate (rather than the network estimate) with higher certainty [18]. We evaluated imprecision using a minimally contextualized framework, setting null for binary outcomes, 1 day for MV duration and length of stay, and 50 mL for fluid balance/urine output at the longest follow-up as minimal clinically important differences [19]. We used informative statements to communicate the certainty in effect estimates [20].

Statistical methods

We calculated standard deviations (SDs) from reported p-values for missing continuous data [21], and imputed means and SDs from medians, ranges, or interquartile ranges [22].

We pooled the data for pairwise meta-analyses using restricted maximum likelihood methods [23]. For dichotomous and continuous outcomes, we reported odds ratios (ORs) or mean differences (MDs), each with 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I² statistic, the chi-squared test, and Forest plots.

We performed Bayesian random-effects NMA using the gemtc package in R, modeling treatment relationships via Markov Chain Monte Carlo methods implemented in rjags with vague (non-informative) priors, allowing the observed data to primarily determine the estimates without strong assumptions on effect size or direction. Three chains were run with 100,000 burn-in iterations and 50,000 sampling iterations. We assessed convergence using the Gelman-Rubin diagnostic, model fit with the deviance information criterion, and between-study heterogeneity using τ².

We planned subgroup analyses based on AKI, presence of heart failure and chronic kidney diseases. We also performed a post hoc sensitivity analysis excluding trials that used oral loop diuretics. Because several subgroup and sensitivity networks were sparse, these subgroup and sensitivity analyses were conducted using a frequentist random-effects network meta-analysis framework (netmeta). Had any subgroup analyses shown evidence of effect modification, we had planned to assess credibility using the ICEMAN tool [24].

We created a summary of findings table including NMA estimates and certainty of evidence, and a second summary table categorizing interventions compared with bolus loop diuretics, which are commonly studied and widely used in clinical practice, differentiating treatments by high- or moderate-certainty evidence or low- or very low–certainty evidence [25].

Results

We identified 31,831 records through electronic searches and included 26 RCTs randomizing 1,652 participants [[26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51]] (eFig. S1).

Median sample size was 50 (range, 18–280), with median male proportion 58.9% (range, 40–90.9%) and mean age ranging from 55.9 to 82.4 years (eTable S2). Thirteen studies (772 patients) enrolled patients with heart failure [26,29,31,33,37,38,[43], [44], [45], [46],48,50,51], 6 studies (688 patients) included post-cardiovascular surgery patients [30,34,35,39,40,49], and 7 studies (263 patients) included heterogeneous ICU populations with fluid overload [27,28,32,36,41,42,47]. Baseline serum creatinine before initiation of diuretic therapy was reported in 15 studies and ranged from 0.94 to 2.29 mg/dL (eTable S2). Only one study reported the prevalence of AKI at the time of diuretic initiation, which was 20%.

For clarity, treatment nodes were labeled according to whether loop diuretics were used alone or in combination with a second diuretic agent (e.g., loop-thiazide). Diuretic therapies included bolus loop administration (bolus loop; 19 studies), continuous furosemide infusion (continuous loop; 15 studies), oral loop furosemide (5 studies)(34, 35, 39, 40, 49), and loop diuretics combined with acetazolamide (loop-acetazolamide; 1 study) [36], thiazides and analogues (loop-thiazide; 2 studies)(28, 50), spironolactone (loop-spironolactone; 3 studies)(27, 40, 49), triamterene (loop-triamterene; 1 study) [50], and tolvaptan (loop-tolvaptan; 8 studies)(29, 33–35, 39, 40, 44, 49). Loop diuretic dosing varied across studies, with oral furosemide doses ranging from 20 to 40 mg/day, bolus doses included from 0.6 to 3 mg/kg/ day or from 40 to 320 mg/day, and continuous infusion dose from 0.05 to 0.75 mg/kg/h or from 40 to 500 mg/day, and one study using azosemide 30 mg daily [39]. Tolvaptan doses ranged from 3.75 to 15 mg/day. Spironolactone doses were 50 or 100 mg/day. Treatment duration ranged from one administration (36) to 9.5 days [49], with one study continuing until hospital discharge (50). For NMA, bolus and oral loop were combined into a single node (bolus loop).

Risk of bias

Twenty-three trials (88.5%) had at least one outcome judged as high or probably high risk of bias in one or more domains, most commonly due to inadequate allocation concealment, followed by concerns regarding random sequence generation and blinding of healthcare providers (eTable S3). Overall risk of bias was low in three trials for mortality and one trial for non-mortality outcomes.

Mortality

Sixteen studies (1166 patients) reported mortality (Fig. 1A). Compared with bolus loop diuretics, loop-acetazolamide (OR 1.75, 95% CrI 0.16–23.6) and loop–thiazide (OR 1.00, 95% CrI 0.14–7.03) may have no effect on mortality (both low certainty) (Table 1; eTables S4 and S5). All other comparisons were very low certainty and showed uncertain effects.

Table 1.

GRADE certainty ratings for mortality between diuretic therapies.

Intervention	Comparator	Direct estimate OR (95% CI)	Indirect estimate OR (95% CI)	Network estimate OR (95% CrI)	GRADE	Narrative summary
Bolus loop	Continuous loop	0.81 (0.48, 1.36)	--	0.80 (0.39, 1.62)	Very low	Bolus loop diuretics have an uncertain effect on mortality compared with continuous loop infusion.
Bolus loop	Loop-acetazolamide	0.62 (0.09, 4.34)	--	0.57 (0.04, 6.43)	Low	Bolus loop diuretics may decrease mortality compared with loop-acetazolamide.
Bolus loop	Loop-thiazide	1.00 (0.24, 4.18)	--	1.00 (0.14, 7.03)	Low	Bolus loop diuretics may have no effect on mortality compared with loop-thiazide.
Bolus loop	Loop-tolvaptan	0.31 (0.03, 3.17)	--	70535 (0.00, 6.1 × 10)	Very low	Bolus loop diuretics have an uncertain effect on mortality compared with loop-tolvaptan.
Bolus loop	Tolvaptan	1.07 (0.11, 10.4)	--	0.24 (0.01, 3.37)	Very low	Bolus loop diuretics have an uncertain effect on mortality compared with tolvaptan.
Continuous loop	Loop-acetazolamide	--	0.76 (0.10, 5.75)	0.71 (0.05, 8.87)	Very low	Continuous loop infusion has an uncertain effect on mortality compared with loop-acetazolamide.
Continuous loop	Loop-thiazide	--	1.24 (0.27, 5.67)	1.26 (0.16, 9.98)	Very low	Continuous loop infusion has an uncertain effect on mortality compared with loop-thiazide.
Continuous loop	Loop-tolvaptan	--	1.32 (0.13, 13.6)	88116 (0.00, 7.9 × 10)	Very low	Continuous loop infusion has an uncertain effect on mortality compared with loop-tolvaptan.
Continuous loop	Tolvaptan	--	0.38 (0.04, 4.15)	0.29 (0.01, 4.63)	Very low	Continuous loop infusion has an uncertain effect on mortality compared with tolvaptan.
Loop-acetazolamide	Loop-thiazide	--	--	1.77 (0.08, 44.7)	Very low	Loop-acetazolamide has an uncertain effect on mortality compared with loop-thiazide.
Loop-acetazolamide	Loop-tolvaptan	--	1.73 (0.09, 34.7)	126614 (0.00, 1.0 × 10)	Very low	Loop-acetazolamide has an uncertain effect on mortality compared with loop-tolvaptan.
Loop-acetazolamide	Tolvaptan	--	0.50 (0.02, 10.5)	0.40 (0.01, 16.8)	Very low	Loop-acetazolamide infusion has an uncertain effect on mortality compared with tolvaptan.
Loop-thiazide	Loop-tolvaptan	--	1.07 (0.07, 15.6)	69154 (0.00, 6.0 × 10)	Very low	Loop-thiazide has an uncertain effect on mortality compared with loop-tolvaptan.
Loop-thiazide	Tolvaptan	--	0.31 (0.02, 4.75)	0.23 (0.00, 6.48)	Very low	Loop-thiazide has an uncertain effect on mortality compared with loop-thiazide.
Loop-tolvaptan	Tolvaptan	--	0.29 (0.01,–7.51)	0.00 (0.00, 4.1 × 10)	Very low	Loop-tolvaptan has an uncertain effect on mortality compared with loop-tolvaptan.

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Abbreviations: CI, confidence interval; CrI, credible interval.

Legends for Table 1: Results are presented as odds ratios (ORs) with 95% credible intervals. ORs greater than 1 indicate higher mortality risk with the intervention relative to the comparator, whereas ORs less than 1 indicate lower mortality risk with the intervention relative to the comparator.

IMV duration

Three studies (320 patients) reported MV duration (eFigure S2A). Compared with loop-tolvaptan, bolus loop (MD 0.05 days fewer, 95% CI 1.08 fewer to 0.96 more) and loop–spironolactone (MD 0.58 days more, 95% CI 1.01 fewer to 2.15 more) may have no effect on MV duration (both low certainty) (eTables S6 and S7). The other comparisons were of very low certainty and showed an uncertain effect.

Incidence of acute kidney injury and need for RRT

Eleven studies (1001 patients) reported AKI incidence (Fig. 1B). Tolvaptan monotherapy may reduce AKI compared with bolus loop diuretic (OR 0.12, 95% CrI 0.01–0.87, low certainty), and continuous loop diuretic infusion (OR 0.09, 95% CrI 0.01–0.84, low certainty). Also, compared with the loop–tolvaptan combination, tolvaptan may decrease AKI (OR 0.13, 95% CrI 0.01–1.12, low certainty) (Table 2; eTables S8 and S9). All other comparisons were based on very low certainty evidence with uncertain effects. Five studies (645 patients) reported the need for RRT (eFigure S2B), however all comparisons were very low certainty and showed uncertain effects (eTables S10 and S11).

Table 2.

GRADE certainty ratings for the incidence of acute kidney injury between diuretic therapies.

Intervention	Comparator	Direct estimate OR (95% CI)	Indirect estimate OR (95% CI)	Network estimate OR (95% CrI)	GRADE	Narrative summary
Bolus loop	Continuous loop	0.82 (0.46, 1.48)	--	0.80 (0.33, 1.88)	Very low	Bolus loop diuretics have an uncertain effect on AKI compared with continuous loop infusion.
Bolus loop	Loop-acetazolamide	1.00 (0.17, 5.98)	--	0.99 (0.10, 10.1)	Very Low	Bolus loop diuretics have an uncertain effect on AKI compared with loop-acetazolamide.
Bolus loop	Loop-tolvaptan	1.12 (0.51, 2.43)	--	1.12 (0.48, 2.43)	Very low	Bolus loop diuretics have an uncertain effect on AKI compared with loop-tolvaptan.
Bolus loop	Tolvaptan	7.00 (1.38, 35.5)	--	8.43 (1.15, 94.7)	Low	Bolus loop diuretics may increase AKI compared with tolvaptan.
Continuous loop	Loop-acetazolamide	--	1.22 (0.19, 7.98)	1.24 (0.11, 14.6)	Very low	Continuous loop infusion has an uncertain effect on AKI compared with loop-acetazolamide.
Continuous loop	Loop-tolvaptan	--	1.36 (0.51, 3.59)	1.39 (0.42, 4.42)	Very low	Continuous loop infusion has an uncertain effect on AKI compared with loop-tolvaptan.
Continuous loop	Tolvaptan	--	8.51 (1.52, 47.8)	10.6 (1.19, 135)	Low	Continuous loop infusion may increase AKI compared with tolvaptan.
Loop-acetazolamide	Loop-tolvaptan	--	1.12 (0.16, 7.86)	1.12 (0.09, 12.7)	Very low	Loop-acetazolamide has an uncertain effect on AKI compared with loop-tolvaptan.
Loop-acetazolamide	Tolvaptan	--	7.00 (0.63, 78.4)	8.49 (0.40, 243)	Very low	Loop-acetazolamide has an uncertain effect on AKI compared with tolvaptan.
Loop-tolvaptan	Tolvaptan	--	6.27 (1.04, 38.0)	7.65 (0.90, 97.5)	Low	Loop-tolvaptan may increase AKI compared with tolvaptan.

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Abbreviations: AKI, acute kidney injury; CI, confidence interval; CrI, credible interval.

Legend for Table 2: Results are presented as odds ratios (ORs) with 95% credible intervals. ORs greater than 1 indicate a higher risk of acute kidney injury with the intervention relative to the comparator, whereas ORs less than 1 indicate a lower risk with the intervention relative to the comparator.

Length of stay

Eleven studies (899 patients) reported ICU length of stay (eFigure S2C). Compared with bolus loop administration, continuous furosemide infusion may increase ICU stay (MD 1.56 days more, 95% CrI 0.02 fewer to 3.16 more, low certainty), while the loop–tolvaptan combination probably had no effect on ICU length of stay (MD 0.14 days fewer, 95% CrI 0.75 fewer to 0.47 more, moderate certainty) (eTables S12 and S13). Compared with continuous infusion, the loop–tolvaptan combination may reduce ICU stay (MD 1.69 days fewer, 95% CrI 0.11 fewer to 3.28 fewer, low certainty). Compared with the loop–spironolactone combination, the loop–tolvaptan combination may have no effect on ICU length of stay (MD 0.50 days fewer, 95% CrI 1.79 fewer to 0.79 more, low certainty). All other comparisons were of very low certainty and showed uncertain effects.

Eleven studies (999 patients) reported hospital length of stay (eFigure S2D) however all comparisons had uncertain effects and based on very low certainty evidence (eTables S14 and S15).

Urine output and fluid balance at the longest follow-up

Twenty studies (1206 patients) reported urine output (Fig. 1C). Due to incoherence for this outcome, we present the higher certainty estimate between the direct or indirect estimate rather than the network estimate (Table 3; eTables S16 and S17). The loop–tolvaptan combination probably increases urine output (MD direct estimate 3174 mL, 95% CrI 1648 fewer to 4700 more, moderate certainty) compared with loop-spironolactone. All other comparisons were very low certainty and showed uncertain effects.

Table 3.

GRADE certainty ratings for differences in urine output at the longest follow-up between diuretic therapies.

Intervention	Comparator	Direct estimate MD (95% CI)	Indirect estimate MD (95% CI)	Network estimate MD (95% CrI)	GRADE	Narrative summary
Bolus loop	Continuous loop	−194 (−623, 235)	2895 (759, 5031)	−22.1 (−297, 253)	Very low	Bolus loop diuretics have an uncertain effect on urine output compared with continuous loop infusion.
Bolus loop	Loop-acetazolamide	−35.7 (−745, 673)	--	−7.13 (−285, 266)	Very low	Bolus loop diuretics have an uncertain effect on urine output compared with loop-acetazolamide.
Bolus loop	Loop-spironolactone		−217 (−1759, 1326)	−9.51 (−206, 186)	Very low	Bolus loop diuretics have an uncertain effect on urine output compared with loop-spironolactone.
Bolus loop	Loop-thiazide	−35.7 (−745, 673)	--	−9.37 (−286, 263)	Very low	Bolus loop diuretics have an uncertain effect on urine output compared with loop-thiazide.
Bolus loop	Loop-triamterene	--	−1580 (−3116, −44.0)	−8.05 (−286, 268)	Very low	Bolus loop diuretics have an uncertain effect on urine output compared with loop-triamterene.
Bolus loop	Loop-tolvaptan	−22.3 (−1504, 1459)	−3391 (−5560, −1221)	−2.12 (−277, 277)	Very low	Bolus loop diuretics have an uncertain effect on urine output compared with loop-tolvaptan.
Bolus loop	Tolvaptan	821 (136, 1506)	--	−11.3 (−287, 268)	Very low	Bolus loop diuretics have an uncertain effect on urine output compared with tolvaptan.
Continuous loop	Loop-acetazolamide	--	−619 (−1565, 327)	15.0 (−262, 290)	Very low	Continuous loop infusion has an uncertain effect on urine output compared with loop-acetazolamide.
Continuous loop	Loop-spironolactone	−22.3 (−1504, 1459)	3067 (1470, 4664)	12.6 (−183, 208)	Very low	Continuous loop infusion has an uncertain effect on urine output compared with loop-spironolactone.
Continuous loop	Loop-thiazide	--	159 (−670, 987)	12.7 (−263, 288)	Very low	Continuous loop infusion has an uncertain effect on urine output compared with loop-thiazide.
Continuous loop	Loop-triamterene	−1386 (−2861, 89.2)	--	14.1 (−267, 289)	Very low	Continuous loop infusion has an uncertain effect on urine output compared with loop-triamterene.
Continuous loop	Loop-tolvaptan	--	−3196 (−5323, −1069)	20.0 (−256, 293)	Very low	Continuous loop infusion has an uncertain effect on urine output compared with loop-tolvaptan.
Continuous loop	Tolvaptan	--	1015 (207, 1823)	10.8 (−268, 289)	Very low	Continuous loop infusion has an uncertain effect on urine output compared with tolvaptan.
Loop-acetazolamide	Loop-spironolactone	--	596 (−1161, 2354)	−2.38 (−197, 194)	Very low	Loop-acetazolamide has an uncertain effect on urine output compared with loop-spironolactone.
Loop-acetazolamide	Loop-thiazide	--	777 (−324, 1879)	−2.23 (−280, 273)	Very low	Loop-acetazolamide has an uncertain effect on urine output compared with loop-thiazide.
Loop-acetazolamide	Loop-triamterene	--	−767 (−2520, 985)	−0.91 (−277, 280)	Very low	Loop-acetazolamide has an uncertain effect on urine output compared with loop-triamterene.
Loop-acetazolamide	Loop-tolvaptan	--	512 (−354, 1378)	5.02 (−271, 286)	Very low	Loop-acetazolamide has an uncertain effect on urine output compared with loop-tolvaptan.
Loop-acetazolamide	Tolvaptan	--	1634 (548, 2720)	−4.16 (−280, 277)	Very low	Loop-acetazolamide has an uncertain effect on urine output compared with tolvaptan.
Loop-spironolactone	Loop-thiazide	--	181 (−1517, 1879)	0.15 (−196, 191)	Very low	Loop-spironolactone has an uncertain effect on urine output compared with loop-thiazide.
Loop-spironolactone	Loop-triamterene	--	−1364 (−3454, 727)	1.47 (−198, 203)	Very low	Loop-spironolactone has an uncertain effect on urine output compared with loop-triamterene.
Loop-spironolactone	Loop-tolvaptan	−3174 (−4700, −1648)	−84.4 (−1639, 1470)	−3174 (−4700, −1648)^*	Moderate	Loop-spironolactone has an uncertain effect on urine output compared with loop-tolvaptan.
Loop-spironolactone	Tolvaptan	--	1038 (−650, 2725)	−1.78 (−199, 196)	Very low	Loop-spironolactone has an uncertain effect on urine output compared with tolvaptan.
Loop-thiazide	Loop-triamterene	--	−1545 (−3237, 147)	1.32 (−273, 281)	Very low	Loop-thiazide has an uncertain effect on urine output compared with loop-triamterene.
Loop-thiazide	Loop-tolvaptan	--	−265 (−1001, 470)	7.25 (−264, 284)	Very low	Loop-thiazide has an uncertain effect on urine output compared with loop-tolvaptan.
Loop-thiazide	Tolvaptan	--	857 (−129, 1843)	−1.93 (−275, 271)	Very low	Loop-thiazide has an uncertain effect on urine output compared with tolvaptan.
Loop-triamterene	Loop-tolvaptan	--	−1810 (−4399, 778)	5.93 (−277, 285)	Very low	Loop-triamterene has an uncertain effect on urine output compared with loop-tolvaptan.
Loop-triamterene	Tolvaptan	--	2401 (719, 4083)	−3.25 (−285, 273)	Very low	Loop-triamterene has an uncertain effect on urine output compared with tolvaptan.
Loop-tolvaptan	Tolvaptan	--	1122 (410, 1834)	−9.18 (−289, 267)	Very low	Loop-tolvaptan has an uncertain effect on urine output compared with tolvaptan.

Open in a new tab

Abbreviations: CI, confidence interval; CrI, credible interval.

Legend for Table 3: Results are presented as differences (days) in the urine output at the longest follow-up (95% credible intervals). Negative effect estimates favor the treatment listed in the intervention column; positive effect estimates favor the comparator.

Incoherence: Due to the incoherence, a direct estimate with a 95% confidence interval was used.

Four studies (128 patients) reported fluid balance (eFigure S2E). Continuous loop infusion had an uncertain effect compared with bolus loop (MD 76.2 mL, CrI 223 fewer to 375 more, very low uncertainty). All other comparisons were very low certainty and showed uncertain effects (eTables S18 and S19).

Adverse effects

Four studies (191 patients) and three reported (313 patients) reported hypokalemia, and atrial fibrillation or atrial flutter, respectively (eFigures S2F and 2G). All comparisons were very low certainty and therefore uncertain (eTables S20-S23).

Subgroup and sensitivity analyses

Insufficient trial-level data precluded subgroup analyses by AKI and chronic kidney disease. In subgroup analyses based on presence of heart failure, there was no evidence of effect modification (eTable S24). Of note, we could only perform this subgroup analysis for some comparisons and outcomes owing to limited data availability. In the sensitivity analysis excluding trials that examined oral loop diuretics, the direction and magnitude of treatment effects was largely unchanged (eTable S25).

Summary of findings

A GRADE Summary Table can be found in Table 4.

Table 4.

Desirable and undesirable effects of diuretic drugs compared with bolus loop administration.

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Abbreviations: MD, mean difference; OR, odds ratio.

Table Legend: This study adopts a minimally contextualized framework incorporating predefined decision thresholds and a null effect to evaluate and classify diuretic agents according to their relative effectiveness and potential harm. In the first step, drugs whose point estimates lie above or below the decision threshold compared with standard treatments are designated as “most effective” or “most harmful,” respectively. In the next step, agents within these categories that are less favorable than at least one other drug in the same group, as indicated by point estimates below and 95% credible intervals that do not include the null effect, are designated as “intermediately effective” or “intermediately harmful.” Numerical values in parentheses represent the 95% credible intervals, unless otherwise specified.

Discussion

This NMA examining diuretic strategies for fluid removal in critically ill adults found bolus loop diuretics appeared comparable to alternate strategies for patient-important outcomes, but evidence certainty was generally low or very low certainty. For most other comparisons, we found an uncertain effect on mortality, IMV duration, AKI, need for RRT, length of stay, urine output, fluid balance or adverse events. Tolvaptan monotherapy was associated with a lower risk of AKI, however, no studies have examined its effect on the need for RRT.

Recent NMAs examining diuretic therapies in acute heart failure (AHF) provide a useful context [[52], [53], [54]]. First, adjunctive therapies (acetazolamide, thiazides, or tolvaptan) increased urine output or weight reduction compared with loop diuretic monotherapy in AHF, albeit with small magnitudes of effect. The studies in patients with heart failure are larger and therefore have more precision to examine these outcomes which may explain the more uncertain effects in critically ill patients. Consistent with the findings of this analysis, the heart failure studies found that combination diuretic had an inconclusive effect on hospital length of stay and no effect on mortality.

The subgroup analyses based on heart failure failed to demonstrate credible effect modification. Rather, we found that the evidence base is structured differently across populations, with some key interventions, most notably tolvaptan monotherapy, only studied in trials of heart failure patients. The sensitivity analysis excluding oral loop therapy did not substantially change results or conclusions. Overall, these findings support a cautious, population-specific approach to diuretic therapy.

We found that tolvaptan monotherapy may decrease AKI compared with bolus or continuous loop infusion. Intensification of diuretics targeting the loop of Henle can cause rapid volume and electrolyte loss, reducing effective circulating volume, activating the renin-angiotensin system (RAS) and sympathetic nervous system, decreasing renal perfusion and intraglomerular pressure, and increasing compensatory distal tubular sodium reabsorption, thereby increasing AKI risk [55,56]. Conversely, tolvaptan induces selective aquaresis via V2 antagonism, preserving electrolyte balance while relieving congestion, suppressing RAS activation, and maintaining renal perfusion, potentially reducing kidney injury [57]. Previous meta-analyses reported similar findings [58,59]; however, findings from this review were derived from trials in patients with acute decompensated heart failure or postoperative cardiac surgery and did not translate into reduced RRT or mortality. Accordingly, the apparent benefit of tolvaptan in reducing AKI should be interpreted as population-specific and hypothesis-generating rather than as evidence of benefit across a general critically ill population. Further research examining the effect of tolvaptan is needed in broader critically ill populations. In fact, this drug is not available in some jurisdictions due to cost or regulatory approval and depending on the results of these larger studies this may need to be re-evaluated.

Commonly used intensified diuretic strategies, including continuous loop diuretic infusion and combination diuretic therapy, had uncertain impacts on urine output without improvements in other patient-important outcomes. A possible signal of increased AKI was observed with continuous loop infusion compared with bolus loop, though the certainty of the evidence was very low. Although continuous loop infusion may have increased ICU length of stay compared with bolus administration, this finding was based on low-certainty evidence and should be interpreted cautiously. It may partly reflect differences in protocolized delivery, including longer continuation or weaning of infusions, rather than a direct effect of the intervention itself. While clinicians may escalate to loop infusion or combination therapies for fluid removal in critically ill patients, the findings of this analysis should provide caution to this approach. These findings support cautious, individualized fluid removal rather than routine escalation to continuous infusion or combination diuretic therapy. The current evidence should inform equipoise and future trial design rather than mandate a specific diuretic strategy across all critically ill adults. If future RCTs confirm finding that initiating continuous loop diuretics or adding a second agent is not helpful and may be harmful, then rather than escalating diuretic therapy, consideration of ultrafiltration may be warranted. This NMA comprehensively evaluated diuretic strategies across diverse ICU populations irrespective of fluid therapy phases, extending beyond the recent ESICM guidelines’ post-resuscitation focus. The findings reinforce the ESICM guideline recommendations that emphasize judicious, protocolized fluid de-resuscitation guided by individualized patient assessment, rather than reliance on specific diuretic agent or administration strategy.

The findings of this NMA have important implications for future research. We need well-powered randomized trials examining optimal diuretic therapies and focusing on patient-centered outcomes, rather than short-term physiological endpoints. Comparative trials of aquaretic versus natriuretic strategies and those evaluating combination therapies may help inform renal-safe approaches to fluid removal in the critically ill which may impact long-term outcomes. Since the direct purpose of diuretics is to increase urine output, it is also important to consider whether their use affects the need for RRT to achieve appropriate fluid removal.

The strengths of this study include a comprehensive search strategy, the use of the GRADE framework to assess the certainty of evidence and contextualize results, the use of NMA methods to compare multiple diuretic strategies, and a focus on critically ill patients, a population underrepresented in prior syntheses. Incorporating both efficacy and safety outcomes provides a balanced assessment of benefits and harms. This study also has several limitations. First, heterogeneity in dosing regimens, administration routes, and treatment duration across studies may have introduced clinical heterogeneity within treatment nodes. Moreover, the applicability of these findings to more general ICU populations is limited because most included trials enrolled patients with heart failure or post-cardiovascular surgery. We, however, accounted for this heterogeneity in GRADE assessments, especially if translated into statistical heterogeneity or intransitivity. In addition, the included trials enrolled clinically heterogeneous medical and surgical populations, whose pathophysiology and treatment goals may differ. However, despite this heterogeneity in population, the unifying objective in all studies was fluid removal comparing various diuretic strategies. Furthermore, some subgroup (e.g. based on presence of heart failure) were limited by sparse networks, insufficient trial-level data, and the selective availability of specific comparisons within certain populations, whereas others (e.g. based on presence of AKI or individual study risk of bias) were not possible based on the same rationale. Therefore, the applicability of our findings to general ICU populations may be limited. Second, many outcomes were informed by a small number of studies or sparse events, resulting in imprecise estimates with wide credible intervals [60,61]. The small number of studies available for each outcomes highlights the need for a core outcome set in this research area. Third, limited reporting of treatment locations (ward versus ICU) may have excluded potentially relevant studies.

Conclusions

Available evidence comparing diuretic strategies for active fluid removal in critically ill adults is limited, clinically heterogeneous, and generally of low or very low certainty. Bolus loop diuretics may be comparable to alternate diuretic strategies for patient important outcomes in critically ill adults. While tolvaptan monotherapy may decrease acute kidney injury, its effect on subsequent RRT requirements and mortality remain uncertain. Well-powered randomized trials prioritizing patient-important outcomes over short-term physiological endpoints are needed to guide clinical decision-making.

Author contributions

Akira Kuriyama: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Writing - Original Draft, Writing - Review & Editing, Visualization, Project administration

Kamil Polok: Data curation, Writing - Review & Editing

Nikita Malhotra: Data curation, Writing - Review & Editing

Naoyuki Kuse: Data curation, Writing - Review & Editing

Tyler Pitre: Formal analysis, Writing - Review & Editing

Devan Lakhanpal: Data curation, Writing - Review & Editing

Rao Sun: Data curation, Writing - Review & Editing

Kapil Dev Soni: Data curation, Writing - Review & Editing

Kaitryn Campbell: Resources, Writing - Review & Editing

Lisa D. Burry: Writing - Review & Editing

Edward G. Clark: Writing - Review & Editing

Kimberley Lewis: Writing - Review & Editing

Morten Hylander Møller: Writing - Review & Editing

Hayley B. Gershengorn: Writing - Review & Editing

Bram Rochwerg: Conceptualization, Methodology, Writing - Review & Editing, Supervision

Consent for publication

Not applicable.

Ethics approval and consent to participate

This study is a systematic review, and therefore ethics approval and informed consent were not required.

Funding

There is no funding source for this study.

Funding

The authors have no external funding for this study.

Availability of data and materials

The datasets generated and analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

Declaration of competing interest

Outside the submitted work, HBG reports grants from the NIH (R01 s on ICU staffing, paid to institution), received travel support for speaking engagements at professional society meetings from ISICEM, CHEST, SCCM, and ATS, as well as travel support for visiting professorships from Cornell and other universities. Additionally, she serves as the Editor-in-Chief of CHEST Critical Care, for which she receives payment for editorial duties. NK receives a Japanese Respiratory Society Fellowship Grant. All the other authors disclosed no conflicts of interest to declare.

Acknowledgements

The authors would like to sincerely thank Drs. Akinori Maeda, Abid Kuchay, Bancha Satirapoj, Pongsathorn Gojaseni, Rui-Qiang Zheng, and Taher Entezari-Maleki for kindly providing the information from their studies. The authors used the following software to assist with the analysis:: Pitre T. CoreSR: an AI-assisted platform for systematic review, meta-analysis, network meta-analysis, and GRADE assessment [software]. Toronto (ON): CoreSR; 2026. Available from: https://coresr.ai.

Footnotes

^{Appendix A}

Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.aicoj.2026.100120.

Appendix A. Supplementary data

The following are Supplementary data to this article:

mmc1.docx^{(1MB, docx)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

mmc1.docx^{(1MB, docx)}

Data Availability Statement

The datasets generated and analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

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PERMALINK

Diuretic therapy for critically ill patients: a systematic review and network meta-analysis

Akira Kuriyama

Kamil Polok

Nikita Malhotra

Naoyuki Kuse

Tyler Pitre

Devan Lakhanpal

Rao Sun

Kapil Dev Soni

Kaitryn Campbell

Lisa D Burry

Edward G Clark

Kimberley Lewis

Morten Hylander Møller

Hayley B Gershengorn

Bram Rochwerg

Abstract

Background

Methods

Results

Conclusions

Introduction

Methods

Eligibility criteria

Information sources and search strategy

Study selection

Data collection process and items

Outcomes

Risk of bias

Certainty of evidence

Statistical methods

Results

Risk of bias

Mortality

Fig. 1.

Table 1.

IMV duration

Incidence of acute kidney injury and need for RRT

Table 2.

Length of stay

Urine output and fluid balance at the longest follow-up

Table 3.

Adverse effects

Subgroup and sensitivity analyses

Summary of findings

Table 4.

Discussion

Conclusions

Author contributions

Consent for publication

Ethics approval and consent to participate

Funding

Funding

Availability of data and materials

Declaration of competing interest

Acknowledgements

Footnotes

Appendix A. Supplementary data

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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