Publication

• Title: Vasopressors or Fluids in Early Septic Shock
• Acronym: ARISE FLUIDS
• Year: 2026
• Journal published in: New England Journal of Medicine
• Citation: The ARISE FLUIDS Investigators, the ANZICS Clinical Trials Group, and the ACEM Clinical Trials Network. Vasopressors or fluids in early septic shock. N Engl J Med. Published online June 11, 2026.

Context & Rationale

• Background

  Septic shock resuscitation has traditionally prioritised early intravenous crystalloid, with vasopressors introduced when hypotension or hypoperfusion persists after fluid administration.
  
  Contemporary guidelines still support an initial crystalloid strategy, but with low-certainty recommendations, increased emphasis on individualisation, and recognition that immediate concurrent vasopressors plus fluid may be appropriate in unstable shock.¹²
  
  The biological rationale for fluid-sparing resuscitation is plausible: excessive positive fluid balance may worsen pulmonary oedema, tissue oedema, endothelial injury, mechanical ventilation exposure, and organ dysfunction.
  
  The opposing concern is equally plausible: early vasopressors before adequate intravascular volume expansion may increase vasoconstriction in underfilled vascular beds, compromise regional perfusion, and shift care to monitored environments with greater resource requirements.
  
  Australian and New Zealand observational data showed substantial variation in fluid volume and vasopressor timing for ED patients with sepsis and hypotension, demonstrating clinical equipoise and feasibility for a regional trial.³
  
  The REFRESH pilot trial showed that a restricted-fluid and early-vasopressor strategy could be delivered in the ED and could separate fluid exposure, but it was small, open-label, and not powered for patient-centred outcomes.⁴
• Research Question/Hypothesis

  ARISE FLUIDS tested whether a strategy of restricted intravenous fluid volume and earlier vasopressor use, compared with greater initial fluid volume and later vasopressor use, would increase days alive and out of hospital to day 90 in adults presenting to the ED with early septic shock.
  
  The trialists hypothesised that reducing early fluid exposure while supporting blood pressure earlier with vasopressors would improve patient-centred outcomes.
• Why This Matters

  The early ED phase is when the 30 mL/kg fluid recommendation is most often operationalised, yet high-quality trial evidence for the initial fluid-volume decision has been limited.
  
  ARISE FLUIDS was designed to test the decision clinicians actually face after the first litre of fluid: give more fluid now, or stop escalating fluids and start vasopressors earlier.
  
  The trial is especially important because it measured days alive and out of hospital, a patient-centred endpoint incorporating survival, illness burden, hospitalisation, and readmission rather than using only a mortality endpoint in a setting with falling sepsis mortality.

Design & Methods

• Research Question: In adults presenting to the emergency department with early septic shock after 1000 to 2000 mL of intravenous fluid, does a restricted-fluid strategy with earlier vasopressors, compared with a greater-fluid strategy with later vasopressors, increase days alive and out of hospital to day 90?
• Study Type: Investigator-initiated, multicentre, open-label, randomised, parallel-group, superiority trial conducted in 51 metropolitan, regional, and rural sites in Australia, New Zealand, and Ireland.
• Population:
  • Adults aged ≥18 years presenting to the ED with clinically suspected infection.
  • Patients had to have persistent hypotension, defined as systolic blood pressure <90 mm Hg or mean arterial pressure <65 mm Hg, despite ≥1000 mL total intravenous fluid bolus administration over ≤60 minutes, including prehospital boluses.
  • Patients also required arterial or venous lactate >2.0 mmol/L and commencement of at least one intravenous antimicrobial agent.
  • All inclusion criteria had to be met within 6 hours of ED presentation, and randomisation had to occur within 2 hours of meeting the final inclusion criterion.
  • Major exclusions included pregnancy, transfer from another acute-care facility, hypotension suspected to be non-septic, >2000 mL total intravenous fluid before randomisation, more than 6 hours since ED presentation, more than 2 hours since the final inclusion criterion, clinician judgement that either strategy was unsuitable, inability to deliver the trial protocol, immediate surgery, treatment limitation, imminent or inevitable death, underlying disease making survival to day 90 unlikely, inability to follow up to day 90, or previous enrolment.
• Intervention:
  • The vasopressor group received a restricted-fluid and early-vasopressor strategy.
  • Intravenous fluid resuscitation was stopped after randomisation.
  • Vasopressor therapy was started immediately for persisting hypotension or hypoperfusion and titrated to a clinician-selected mean arterial pressure target.
  • Vasopressor type, route, dose adjustment, and target pressure were left to the treating clinician.
  • Peripheral vasopressor administration was permitted.
  • Fluid boluses of 250 mL were allowed if clinically indicated, including refractory hypotension, persistent hypoperfusion, delayed capillary refill, lactate >4 mmol/L or rising despite at least 2 hours of resuscitation, persistent tachycardia, or oliguria <0.5 mL/kg/h for at least 2 hours.
  • Maintenance fluids were discouraged.
  • The assigned strategy was delivered for at least 6 hours and up to 24 hours while the patient remained in a critical care area.
• Comparison:
  • The fluids group received a greater-fluid and later-vasopressor strategy.
  • An initial intravenous fluid bolus of up to 1000 mL was given within 60 minutes after randomisation if the mean arterial pressure remained below target or if hypoperfusion persisted.
  • Additional 500 mL boluses were recommended for ongoing hypotension or hypoperfusion.
  • A total fluid dose of 30 mL/kg within 3 hours of ED presentation was recommended unless clinically contraindicated.
  • Vasopressors were started later if the clinician judged that the intravascular volume had been restored or that arterial pressure was not fluid responsive.
  • Patients in extremis in either group could receive concurrent fluids and vasopressors.
  • All other care, including fluid type, vasopressor type, central or peripheral access, antimicrobial therapy, corticosteroids, source control, mechanical ventilation, and ICU admission, was determined by treating clinicians.
• Blinding: The intervention could not be blinded because it required visible changes in fluid delivery and vasopressor initiation. Patients and treating clinicians were aware of allocation. The management committee and trial statisticians remained unaware of treatment allocation until blinded analyses of primary and secondary outcomes had been completed and accepted.
• Statistics: The protocol and statistical analysis plan were published before completion of recruitment.⁵⁶ A total of 1000 patients was required to provide 90% power to detect a 7-day absolute difference in days alive and out of hospital to day 90, using a two-sided 5% significance level, allowing for a 15% inflation factor for non-parametric distribution and 5% loss to follow-up. Analyses followed the intention-to-treat principle, excluding patients for whom consent to use all data was not obtained. The primary outcome was analysed using quantile mixed-effects regression at the median, with trial site as a random effect.
• Follow-Up Period: The primary outcome was assessed to day 90. Secondary outcomes included mortality at day 28 and day 90, days alive and at home to day 90, organ-support-free days to day 28, and longer-term disability outcomes planned at 6 and 12 months.

Key Results

This trial was not stopped early. A planned DSMC interim analysis after completion of day-90 follow-up in the first 500 patients recommended that recruitment continue unchanged.

• ARISE FLUIDS achieved the intended intervention contrast: less fluid, earlier vasopressors, and more peripheral vasopressor use in the vasopressor group.
• Despite this separation, the primary patient-centred outcome was identical: median days alive and out of hospital to day 90 was 76 days in both groups.
• Prespecified subgroup analyses did not identify a credible responder group. For example, the median difference in DAOH90 was −2.00 days in lactate ≥3 mmol/L patients (95% CI −6.88 to 1.63), −1.06 days in APACHE II ≥15 patients (95% CI −5.07 to 1.92), 0.00 days in patients who had received ≥1500 mL before randomisation (95% CI −3.30 to 3.45), and −1.60 days in respiratory-source sepsis (95% CI −8.32 to 4.05). Interaction p values were not reported.

Internal Validity

• Randomisation and Allocation: Randomisation used a secure, password-protected web-based system available 24 hours per day. Allocation was 1:1, stratified by site, and used variable block sizes. Allocation concealment appears robust until assignment.
• Drop out or exclusions: A total of 1000 patients underwent randomisation: 499 to the vasopressor group and 501 to the fluids group. Informed consent for use of data was not obtained for 37 patients, leaving 963 patients in the intention-to-treat analysis: 481 vs 482. Three fluids-group patients were lost to follow-up for the primary outcome, and multiple imputation was used.
• Performance/Detection Bias: The trial was open-label. This was unavoidable for a complex haemodynamic strategy but creates risk of performance bias, especially for ICU admission, timing of discharge, pulmonary oedema recognition, and clinician-triggered interventions. The primary outcome was largely objective, but discharge and readmission are still partly health-system dependent.
• Protocol Adherence: Protocol adherence was high. Among patients alive at 6 hours, the intervention was delivered for less than 6 hours in 27/475 (5.7%) vs 31/476 (6.5%). However, clinically important deviations occurred: 71/481 (14.8%) patients in the vasopressor group received a fluid bolus >250 mL, 13/481 (2.7%) did not have vasopressors commenced for hypotension or hypoperfusion, and 12/482 (2.5%) in the fluids group did not receive a 500 mL bolus for hypotension or hypoperfusion.
• Baseline Characteristics: Groups were well balanced. Median age was 68 vs 69 years; male sex 58.4% vs 62.7%; APACHE II 18 vs 18; modified SOFA 4 vs 4; systolic blood pressure 85 vs 86 mm Hg; lactate 3.3 vs 3.2 mmol/L; prerandomisation fluid 1500 vs 1500 mL; and time from ED presentation to randomisation 2.10 vs 2.10 hours.
• Heterogeneity: Clinical heterogeneity was expected and acceptable for a pragmatic strategy trial. Infection sources included pulmonary, urinary, intra-abdominal, skin and soft tissue, bloodstream, other, and unknown sources. The strategy was tested across metropolitan, regional, and rural settings. Heterogeneity enhances pragmatic relevance but dilutes the possibility that one phenotype, such as fluid-responsive distributive shock or fluid-intolerant cardiac failure, might benefit differentially.
• Timing: The intervention was early. Median time from ED presentation to randomisation was 2.10 hours in both groups, and median time from final eligibility confirmation to randomisation was 0.30 hours in both groups. The vasopressor strategy moved vasopressor initiation earlier: 0.4 hours vs 1.4 hours after randomisation.
• Dose: The trial tested a clinically realistic difference, not an extreme physiology experiment. Patients had already received a median of 1500 mL before randomisation. During the first 6 hours after randomisation, patients received 500 mL vs 1500 mL; by 24 hours, 1140 mL vs 2248 mL. This is a meaningful 1-litre separation, but not a complete fluid-avoidance strategy.
• Separation of the Variable of Interest: Separation was strong. Fluid volume from 0 to 6 hours was 500 mL vs 1500 mL, difference −1000 mL (95% CI −1088 to −884). Fluid volume from 0 to 24 hours was 1140 mL vs 2248 mL, difference −1108 mL (95% CI −1395 to −850). Vasopressor initiation within 24 hours was 86.5% vs 67.6%, difference 18.9 percentage points (95% CI 13.3 to 24.5). Peripheral vasopressor infusion was 71.9% vs 55.4%, difference 16.5 percentage points (95% CI 10.5 to 22.4).
• Key Delivery Aspects: The trial enrolled before completion of a 30 mL/kg strategy, which is exactly where the clinical decision is contested. The control was a guideline-consistent fluid-first strategy rather than substandard care. The intervention allowed clinician override for critical hypotension and hypoperfusion, improving safety but reducing separation.
• Crossover: This was a strategy trial rather than a drug-placebo trial, so crossover is best understood as protocol-permitted rescue and contamination. Vasopressors were already running before randomisation in 57/481 (11.9%) vs 41/482 (8.5%). In the fluids group, 67.6% received vasopressors within 24 hours. In the vasopressor group, 14.8% received a bolus >250 mL. These features reflect real practice but attenuate any pure contrast between “fluids” and “vasopressors”.
• Adjunctive therapy use: Concomitant therapies were broadly similar. Intravenous corticosteroids were used in 192/481 (39.9%) vs 170/482 (35.3%). Source control occurred in 79/481 (16.4%) vs 94/482 (19.5%), with median time to source control 8 vs 7 hours. Antimicrobial timing was rapid in both groups: 0.97 vs 0.85 hours from ED presentation.
• Outcome Assessment: DAOH90 is objective, efficient, and patient-centred, and its use in sepsis trials is supported by association with later health-related quality of life.⁷ However, DAOH90 blends death, length of stay, and readmission, and is sensitive to discharge norms, rehabilitation pathways, and hospital capacity.
• Statistical Rigor: The analysis followed a prespecified SAP, used an intention-to-treat population, accounted for site clustering, handled missing primary-outcome data with multiple imputation, and included prespecified adjusted and sensitivity analyses. Secondary and subgroup outcomes were exploratory and were not adjusted for multiplicity.

Conclusion on Internal Validity: Internal validity is strong for the primary neutral finding because allocation was concealed, follow-up was near complete, the intervention separated fluid and vasopressor exposure, and the primary analysis was prespecified. Internal validity is more limited for clinician-reported complications and process outcomes because treatment was open-label.

External Validity

• Population Representativeness: Participants were typical of high-resource ED patients with early septic shock after initial fluid resuscitation: median age 68 to 69 years, median lactate 3.2 to 3.3 mmol/L, median APACHE II 18, modified SOFA 4, and median 1500 mL fluid before randomisation.
• Geography: Enrolment was overwhelmingly Australasian, with sites in Australia and New Zealand contributing almost all patients and one Irish site contributing one patient. The supplement judged the Australian and New Zealand population broadly representative for patients meeting eligibility criteria, including age, sex, and ethnicity.
• Important exclusions: Applicability is limited for patients transferred from another acute facility, patients who had already received >2 L fluid, patients with treatment limitations, patients needing immediate surgery, patients with non-septic hypotension, patients with imminent death, pregnant patients, and patients unlikely to survive to day 90 from underlying disease.
• Severity: Mortality was lower than in many ICU septic shock cohorts: day-90 mortality was 16.4% vs 14.4%. These results are therefore most applicable to early recognised ED septic shock in systems with rapid antimicrobial treatment, close monitoring, and access to vasopressors.
• Applicability: The findings translate well to EDs and ICUs that can safely administer early peripheral vasopressors, monitor patients in critical care areas, reassess hourly, and support protocolised fluid restriction.
• Resource-limited settings: Generalisability to low-income or resource-limited settings is weaker. Early vasopressor strategies may require monitored beds, infusion pumps, nursing ratios, and policies allowing peripheral vasopressors. In ARISE FLUIDS, ICU admission was higher in the vasopressor group: 76.5% vs 67.8%.

Conclusion on External Validity: External validity is strong for high-resource ED systems managing early septic shock after 1 to 2 litres of fluid. It is limited for later, more severe, already heavily resuscitated, transferred, perioperative, treatment-limited, or resource-constrained populations.

Strengths & Limitations

• Strengths:
  • Large 1000-patient randomised trial in the early ED septic shock window.
  • Multicentre enrolment across 51 metropolitan, regional, and rural sites.
  • Direct test of a bedside strategy decision rather than a single drug or isolated fluid dose.
  • Protocol and SAP published before recruitment completion.
  • Near-complete primary outcome ascertainment.
  • Clinically meaningful separation in both fluid volume and vasopressor timing.
  • Patient-centred primary outcome incorporating survival and hospital burden.
  • Permitted pragmatic clinician discretion for safety, fluid type, vasopressor agent, and route.
• Limitations:
  • Open-label design with risk of performance and ascertainment bias.
  • Pulmonary oedema was clinician-reported and particularly vulnerable to reporting bias.
  • DAOH90 is partly influenced by health-system discharge practices, ward availability, rehabilitation pathways, and readmission thresholds.
  • The trial was powered for a 7-day DAOH90 difference, not for smaller patient-important differences or mortality.
  • The population had relatively low mortality, limiting power to assess survival differences.
  • Patients who had already received >2 L fluid were excluded, limiting applicability to patients recognised later or resuscitated more aggressively before screening.
  • Strategy contamination occurred: many fluids-group patients received vasopressors, and some vasopressor-group patients received larger fluid boluses.
  • The early vasopressor strategy increased ICU admission, an important resource implication in constrained systems.

Interpretation & Why It Matters

• Clinical meaning

  After an initial 1 to 2 litres of fluid in ED septic shock, a strategy of stopping fluid escalation and starting vasopressors earlier did not improve days alive and out of hospital to day 90 compared with a greater-fluid, later-vasopressor strategy.
• Fluid-sparing is safe, but not superior

  The trial supports the safety and feasibility of early vasopressors and lower fluid volumes in monitored settings, but it does not support routine superiority of this approach for patient-centred outcomes.
• The pulmonary oedema signal matters

  Reported pulmonary oedema was lower with early vasopressors, 0.6% vs 5.0%, but because the trial was open-label this is best interpreted as a clinically plausible safety signal rather than definitive proof of benefit.
• Practice impact

  ARISE FLUIDS moves practice away from ideology. It does not vindicate mandatory 30 mL/kg fluid for all patients, and it does not prove that early vasopressors are outcome-improving for all. It supports individualised resuscitation after early recognition, early antimicrobials, and initial fluid loading.

Controversies & Subsequent Evidence

• The 30 mL/kg question is narrowed, not settled. The 2026 Surviving Sepsis Campaign guideline continued to suggest at least 30 mL/kg crystalloid within the first 3 hours for sepsis-induced hypoperfusion or septic shock, but with low-certainty evidence and a remark to consider individual patient characteristics and context.¹ ARISE FLUIDS tested a strategy after 1000 to 2000 mL, not zero-fluid resuscitation, and therefore does not refute the need for initial fluid in early septic shock.
• ARISE FLUIDS aligns with CLOVERS and CLASSIC. CLOVERS enrolled ED patients with sepsis-induced hypotension and was stopped for futility; mortality before discharge home by day 90 was 14.0% vs 14.9% with restrictive vs liberal fluids.⁸ CLASSIC enrolled ICU patients after initial resuscitation and found 90-day mortality of 42.3% vs 42.1% with restricted vs standard fluids.⁹ ARISE FLUIDS fills the remaining ED-specific gap by enrolling before completion of a 30 mL/kg strategy.
• Meta-analytic evidence before ARISE FLUIDS was neutral and imprecise. A 2023 updated systematic review of lower vs higher fluid volumes in adults with sepsis included 13 trials and found little or no mortality difference in low-risk-of-bias trials: RR 0.99; 97% CI 0.89 to 1.10.¹⁰ ARISE FLUIDS adds a large, pragmatic, ED-focused trial to that neutral evidence base.
• Early vasopressors remain physiologically attractive but not outcome-proven as a default. CENSER, a single-centre double-blind trial, found improved shock control by 6 hours with early norepinephrine, 76.1% vs 48.4%, but no statistically significant 28-day mortality difference, 15.5% vs 21.9%.¹¹ A 2025 systematic review found an apparent mortality signal favouring early norepinephrine in RCTs, OR 0.49; 95% CI 0.25 to 0.96, but trial sequential analysis indicated that more data were needed.¹² ARISE FLUIDS materially reduces enthusiasm for routine early vasopressors as an outcome-improving strategy in all early septic shock patients.
• The primary outcome is both strength and controversy. DAOH90 is patient-centred and captures more than mortality, but it may be less intuitive than death, can be system-dependent, and may be insensitive to smaller physiological harms or benefits. The identical median DAOH90 result is compelling, but it should not be overread as proving equivalence for all outcomes.
• The pulmonary oedema result is credible but not definitive. Less pulmonary oedema is biologically consistent with lower fluid exposure and mirrors signals from earlier early-vasopressor work, but open-label reporting and clinician expectation could inflate this difference.
• Resource consequences are central. Early vasopressors increased ICU admission by 8.7 percentage points. In hospitals where vasopressors require ICU-level care, a routine early-vasopressor strategy may increase critical care demand without improving DAOH90.

Summary

• ARISE FLUIDS randomised 1000 ED patients with early septic shock after 1000 to 2000 mL fluid to restricted fluids plus earlier vasopressors or greater fluids plus later vasopressors; 963 were analysed.
• The vasopressor strategy achieved the intended separation: 0–24 hour fluid volume 1140 vs 2248 mL and vasopressor initiation 86.5% vs 67.6%.
• The primary outcome was neutral: DAOH90 76 vs 76 days; median difference 0.0 days; 95% CI −2.7 to 2.7; P=1.00.
• Mortality, organ support, days alive and at home, ventilation, and renal replacement therapy were not improved.
• Pulmonary oedema was reported less often with early vasopressors, 0.6% vs 5.0%, but the open-label design makes ascertainment bias plausible.

Overall Takeaway

ARISE FLUIDS is a practice-shaping ED septic shock strategy trial. It shows that, after initial fluid resuscitation, routinely prioritising earlier vasopressors and lower fluid volumes is feasible and reduces fluid exposure, but does not improve days alive and out of hospital at 90 days compared with a more fluid-forward strategy.

Bibliography

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• 2.Mekontso Dessap A, AlShamsi F, Belletti A, Arabi YM, Bihari S, Cecconi M, et al. European Society of Intensive Care Medicine (ESICM) 2025 clinical practice guideline on fluid therapy in adult critically ill patients: part 2—the volume of resuscitation fluids. Intensive Care Med. 2025;51:461-477.
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• 9.Meyhoff TS, Hjortrup PB, Wetterslev J, Sivapalan P, Laake JH, Cronhjort M, et al; CLASSIC Trial Group. Restriction of intravenous fluid in ICU patients with septic shock. N Engl J Med. 2022;386:2459-2470.
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