Septic shock trial finds fewer fluids and earlier vasopressors no better than standard care

Overview

Updated 1 hour ago

Septic shock treatment rests on a simple rule: give fluids fast and plenty of them. A trial in the New England Journal of Medicine tested the opposite strategy — less fluid, earlier vasopressors — and found patients did just as well.

The ARISE FLUIDS trial randomized 963 patients presenting to emergency departments in Australia and New Zealand. The early-vasopressor group received a median of 1,108 mL less fluid in the first 24 hours, yet both groups spent a median of 76 days alive and out of the hospital in the 90 days after randomization. The only meaningful difference was adverse events: pulmonary edema appeared in 5.0% of the fluid-first group versus 0.6% of the vasopressor-first group.

The result extends a pattern across five trials since 2014: aggressive fluid resuscitation, standard since Emanuel Rivers' 2001 protocol, has failed every head-to-head comparison. The question now is whether emergency departments change how they resuscitate, and whether future trials move toward individualizing treatment rather than picking one universal strategy.

Why it matters

Thousands of septic shock patients a year could avoid excess-fluid complications if emergency departments adopt earlier vasopressor use.

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Key Indicators

76 vs 76

Median days alive and out of hospital at day 90

Identical in both groups; difference 0.0 days, P=1.00

1,108 mL

Less fluid in vasopressor group, first 24 hours

Median difference; 95% CI -1,395 to -850 mL

18.9 pp

Higher vasopressor use with early initiation

86.5% vs 67.6% received vasopressors within 24 hours

0.6% vs 5.0%

Pulmonary edema rate, vasopressor vs fluids group

Significantly lower with early vasopressors, P<0.001

1,000

Patients randomized in ARISE FLUIDS

963 in the intention-to-treat population after consent exclusions

Voices

Curated perspectives — historical figures and your fellow readers.

Ever wondered what historical figures would say about today's headlines?

People Involved

Emanuel Rivers

Critical care physician, author of the 2001 early goal-directed therapy trial

Historical figure whose protocol defined two decades of aggressive fluid resuscitation

Organizations Involved

New England Journal of Medicine

Peer-reviewed medical journal

Publisher of ARISE FLUIDS and the earlier trials in this arc

One of the world's oldest and most cited medical journals.

National Heart, Lung, and Blood Institute

Federal research institute (part of NIH)

Funded the CLOVERS trial

Division of the US National Institutes of Health.

Australian National Health and Medical Research Council

Government funding agency

Co-funder of ARISE FLUIDS

Australia's peak body for supporting health and medical research.

New Zealand Health Research Council

Government funding agency

Co-funder of ARISE FLUIDS

New Zealand's national agency for health research funding.

Timeline

November 2001 October 2026

8 events Latest: Today

Tap a bar to jump to that date

October 2026
Trial results circulate widely among clinicians
Today Reaction

Discussion of ARISE FLUIDS findings spreads through clinical and research communities.
Today
June 2026
ARISE FLUIDS trial published
Research

963-patient trial finds early vasopressors and less fluid match standard care, with fewer cases of pulmonary edema.
June 2026
January 2023
CLOVERS trial published
Research

US trial of 1,563 patients finds no mortality difference between restrictive and liberal fluids in emergency departments.
January 2023
June 2022
CLASSIC trial published
Research

ICU trial finds restrictive fluids no better than a standard approach to septic shock.
June 2022
March 2015
ProMISe trial published
Research

UK trial of 1,260 patients replicates the result, ending the protocolized fluids era.
March 2015
October 2014
ARISE trial published
Research

Australia and New Zealand trial confirms ProCESS findings in 1,600 patients.
October 2014
March 2014
ProCESS trial published
Research

US trial of 1,341 patients finds early goal-directed therapy no better than usual care.
March 2014
November 2001
Rivers publishes early goal-directed therapy trial
Research

Single-center trial shows aggressive fluid resuscitation cuts mortality in severe sepsis, launching the protocol-based resuscitation era.
November 2001

Scenarios

Surviving Sepsis Campaign rewrites fluid guidance

Possible Resolves by End of 2027

Discussed by: Commentators at NephJC and Broome Docs

The Surviving Sepsis Campaign guidelines currently recommend an initial 30 mL/kg fluid bolus for septic shock, with vasopressors as an adjunct. After ARISE FLUIDS and CLOVERS both showed equivalence, the campaign faces pressure to formally endorse earlier vasopressor initiation and individualize fluid volume. An update would mark the first major guideline change toward permissive resuscitation in two decades.

Emergency departments adopt early vasopressors without guideline change

Likely Resolves by End of 2028

Discussed by: Broome Docs, acute care commentators

Even without formal guideline changes, emergency department clinicians may shift practice based on trial results, especially in rural and remote settings where large-volume fluids are logistically harder to administer. Registry data would reveal whether the equivalent outcomes change real-world behavior.

Phenotype-guided resuscitation becomes the next trial frontier

Likely Resolves by End of 2027

Discussed by: NephJC editorial

ARISE FLUIDS and CLOVERS both tested blanket strategies and both found no difference. The next step, per the NephJC analysis, is integrating fluid responsiveness, cardiac function, and congestion to tailor resuscitation per patient. A trial testing this would likely enroll several hundred patients across multiple centers.

Historical Context

3 moments from history that rhyme with this story — and how they unfolded.

November 2001

Rivers Early Goal-Directed Therapy Trial (2001)

Emanuel Rivers published a single-center trial in NEJM showing that aggressive, protocol-driven fluid resuscitation cut mortality in severe sepsis from 46.5% to 30.5%. The protocol became standard care and shaped the Surviving Sepsis Campaign's 30 mL/kg fluid bolus recommendation.

Then

Hospitals worldwide adopted protocolized fluid resuscitation as the default for septic shock.

Now

The recommendation persisted for two decades despite never being reproduced in a multicenter trial.

Why this matters now

ARISE FLUIDS and the trials before it were all designed to test whether Rivers' aggressive approach actually helps. None has found a benefit.

March 2014 - March 2015

ProCESS, ARISE, ProMISe Trials (2014-2015)

Three large trials in the US, Australia, and the UK independently compared protocolized early goal-directed therapy with usual care. All three found no mortality difference, dismantling the central pillar of Rivers' protocol.

Then

The 30 mL/kg bolus recommendation was downgraded, but aggressive fluids remained common practice.

Now

The trials left open the question of whether more conservative fluid strategies might actually be better.

Why this matters now

ARISE FLUIDS directly tested that question in the earliest, emergency-department window — the same setting Rivers studied.

January 2023

CLOVERS Trial (2023)

The 1,563-patient CLOVERS trial randomized US emergency department patients with sepsis-induced hypotension to restrictive fluids with early vasopressors or liberal fluids with later vasopressors. Mortality was identical: 14.0% versus 14.9%.

Then

The trial showed restrictive strategies are safe in the US emergency setting.

Now

CLOVERS established the design template that ARISE FLUIDS then replicated across Australia and New Zealand.

Why this matters now

ARISE FLUIDS is the second large trial to reach the same conclusion, strengthening the case that fluid volume is not the main driver of septic shock outcomes.