Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension
Open accessAbstract
BACKGROUND: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited. METHODS: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed. RESULTS: A total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups. CONCLUSIONS: Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028.).
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Fixed-volume mandates embedded in SEP-1 may conflict with individualized, physiology-driven care, particularly for patients at elevated risk of fluid-related harm.
“fixed-volume mandates embedded in SEP-1 may conflict with individualized, physiology-driven care, particularly for patients at elevated risk of fluid-related harm [22,23].”
From Artificial Intelligence to Facilitate SEP-1 Measure Compliance and Fluid Management in Sepsis (2026) · cites this paper as [23]
The Trial Procedures and protocol diagram (p. 502) allow clinicians to adjust fluids based on a patient's condition and to halt fluids when overload appears. Safety Outcomes reports fewer fluid-overload and pulmonary-edema events in the restrictive group. The paper does not discuss SEP-1 or establish that its fixed-volume mandates conflict with individualized care, including for patients at elevated risk of fluid-related harm. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPrevious studies examining restricted versus liberal fluid strategies had patients enrolled after approximately 30 mL/kg of crystalloid fluid administration.
“While previous studies examining restricted versus liberal fluid strategies had patients enrolled after an approximately 30 mL/kg of crystalloid fluid administration, fixed-volume mandates embedded in SEP-1 may conflict with individualized, physiology-driven care, particularly for patients at elevated risk of fluid-related harm [22,23].”
From Artificial Intelligence to Facilitate SEP-1 Measure Compliance and Fluid Management in Sepsis (2026) · cites this paper as [23]
The Methods describe enrollment after initial treatment with 1–3 liters of intravenous fluid, and Characteristics of the Patients reports a median of 2050 ml before randomization in each group (page not available in our copy). This supports enrollment after fluids but does not establish the claimed approximately 30 ml/kg crystalloid dose. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn emergency department patients with early sepsis-induced hypotension, Shapiro et al. showed that earlier vasopressor use with lower fluid volumes resulted in similar mortality and clinical outcomes as a liberal-fluid approach.
“In the emergency department (ED) patients with early sepsis-induced hypotension, Shapiro et al. showed that earlier vasopressor use with lower fluid volumes resulted in similar mortality and clinical outcomes as a liberal-fluid approach, supporting a physiology-guided strategy [23].”
From Artificial Intelligence to Facilitate SEP-1 Measure Compliance and Fluid Management in Sepsis (2026) · cites this paper as [23]
Earlier vasopressor use was associated with increased intensive care resource utilization.
“Although outcomes were similar, earlier vasopressor use was associated with increased intensive care resource utilization.”
From Artificial Intelligence to Facilitate SEP-1 Measure Compliance and Fluid Management in Sepsis (2026) · cites this paper as [23]
Recent randomized trials in emergency department and intensive care unit populations have not shown a mortality benefit for restrictive versus liberal fluid strategies after initial resuscitation.
“In contemporary high-resource settings, recent randomized trials in emergency department and intensive care unit populations have not shown a mortality benefit for restrictive versus liberal fluid strategies after initial resuscitation [22,23].”
From Artificial Intelligence to Facilitate SEP-1 Measure Compliance and Fluid Management in Sepsis (2026) · cites this paper as [23]
Contemporary trials support equipoise between liberal and restrictive early fluid strategies.
“For hemodynamic management, contemporary trials support equipoise between liberal and restrictive early fluid strategies, reinforcing the rationale for adaptive, physiology-guided resuscitation [22,23].”
From Artificial Intelligence to Facilitate SEP-1 Measure Compliance and Fluid Management in Sepsis (2026) · cites this paper as [23]
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Influential
- Authors
- The National Heart, L.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- The National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2023-02-09
- Volume
- 388
- Issue
- 6
- Pages
- 499-510
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC10685906
- OpenAlex
- W4317677052
- Cited by
- 427
- References
- 33
- Citations by year
- 2026: 128 · 2025: 105 · 2024: 109 · 2023: 85
- FWCI
- 84.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (U01 HL122989, U01 HL122998, U01 HL123004, U01 HL12)
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Hemodynamic Monitoring and Therapy
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Abdominal Surgery and Complications
- Keywords
- sepsis-induced hypotension, fluid resuscitation, restrictive fluid strategy, liberal fluid strategy, vasopressors, intravenous fluids, all-cause mortality
- MeSH terms
- Fluid Therapy, Humans, Hypotension, Time Factors, Vasoconstrictor Agents, Treatment Outcome, Sepsis
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