Fluids first or pressors first in early septic shock: no difference in days alive and out of the hospital, with about half the extra fluid

🎧 Listen: Weekly · Oct 12, from 01:12.

The background

For sepsis-induced hypotension, the Surviving Sepsis Campaign gives a weak recommendation for at least 30 ml per kilogram of intravenous fluid in the first 3 hours. That dose has never had high-quality trial evidence behind it. Nephrologists often meet its consequences on day two: the puffy patient, the wet lungs and the question of whether all that fluid helped. An earlier trial, CLOVERS, found no mortality benefit from a restrictive fluid strategy in sepsis with hypotension.

What the trial did

ARISE FLUIDS is an investigator-initiated, open-label randomized trial run by intensive care and emergency medicine trial networks from Australia and New Zealand, at 51 sites in three countries, from October 2021 to November 2025. It enrolled adults in the emergency department with suspected infection whose systolic pressure was still below 90 mm Hg (or mean arterial pressure below 65) after at least 1 liter of fluid, with a lactate above 2 mmol per liter and antibiotics started. Patients who had already received more than 2 liters, who needed fluid restriction (for example, for heart failure) or who had limits on their care were excluded. Before randomization they had received a median of 1.5 liters.

For up to 24 hours, patients were assigned to one of two strategies:

• Pressors first (restricted fluid): intravenous fluid stopped at randomization and a vasopressor started. A 250-ml bolus was allowed only for a reason: hypotension that wouldn't respond, signs of poor perfusion such as a slow capillary refill, a lactate above 4 or still rising after 2 hours, a persistently fast heart rate, or urine output below 0.5 ml per kilogram per hour for 2 hours.
• Fluids first (usual care): up to 1 liter in the first hour, then 500-ml boluses for persistent hypotension or poor perfusion, with 30 ml per kilogram within 3 hours recommended. A vasopressor was started if the pressure target wasn't reached once the clinician judged the patient fluid-replete or no longer fluid-responsive.

The primary outcome was the number of days alive and out of the hospital over 90 days.

What they found

• 963 patients were analyzed (481 pressors first, 482 fluids first). Over the first 24 hours, the pressors-first group received a median of about 1.1 liters and the fluids-first group about 2.2 liters.
• The separation in vasopressors was smaller: within 24 hours, 86.5% of the pressors-first group and 67.6% of the fluids-first group received one, and the median start was only about an hour earlier (0.4 vs 1.4 hours).
• Main outcome: a median of 76 days alive and out of the hospital in both groups (difference 0.0 days; 95% CI, −2.7 to 2.7).
• Pulmonary edema was reported in 0.6% of the pressors-first group and 5.0% of the fluids-first group.
• Kidney replacement therapy: 6.2% vs 5.2%, not significantly different. Invasive ventilation: 15.4% vs 15.1%. Among ventilated patients, time to first coming off the ventilator was numerically shorter with pressors first (median 45 vs 68 hours) but not significantly different.
• Deaths by day 90: 16.4% vs 14.4% (relative risk 1.14; 95% CI, 0.85 to 1.54), not statistically significant.
• In the first 24 hours, 71.9% of the pressors-first group (vs 55.4% of the fluids-first group) received a vasopressor through a peripheral line, and few complications related to either strategy were reported apart from pulmonary edema. About a third of patients on a vasopressor received metaraminol.

Why it matters

The authors say the results are consistent with CLOVERS, and that enrolling patients in the emergency department before the full 30 ml per kilogram had been given tests the guideline's initial-fluid dose directly. Our take: after the first liter or two, more fluid isn't the only reasonable move. Starting the pressor earlier did no worse on the main outcome, as far as this trial could tell, with about half the extra fluid and possibly less pulmonary edema. For the renal consult on day two, the first-day strategy didn't detectably change how many patients needed dialysis. Our note from practice: many ICUs already start vasopressors through a peripheral line until a central line is in, under their own local policies; the trial's low complication count fits that experience.

Caveats

The trial was open-label, and the authors say the pulmonary edema difference may partly reflect reporting bias: teams who knew a patient got extra fluid may have looked for edema more. It was designed to find a difference, so "no difference detected" is not proof the two strategies are the same. Deaths at 90 days were numerically higher with pressors first; a gap that size could be chance, and the trial wasn't designed to answer it, but it is one more reason not to crown either strategy. The intervention lasted at most 24 hours, people needing fluid restriction were excluded, metaraminol, common in Australia, is not used in the US (our note), and the results may not apply to low-resource settings.

Funding and ties: funded by Australia's Medical Research Future Fund and New Zealand's Health Research Council, with no commercial support. The writing committee was led by Dr. Sandra Peake and Dr. Stephen Macdonald; the paper notes that a member of the writing committee, Professor Rinaldo Bellomo, is deceased.

The source: The ARISE FLUIDS Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group and Australasian College for Emergency Medicine Clinical Trials Network. Vasopressors or Fluids in Early Septic Shock. N Engl J Med 2026;395:1387-1398. doi:10.1056/NEJMoa2516225 Read the original

🎧 Listen: Weekly · Oct 12, from 01:12.

Physician-led, AI-assisted. Dr. Wael Hussein chooses every item NephSpace covers and reviews and edits every story before it is published. The first draft was written in our own words with AI (Claude, by Anthropic) from the full text of the paper and checked against our reading notes; Dr. Hussein then reviewed and edited it. For education and information only, not medical advice. Please talk to your own physician or care team about your health. Clinicians: read the original before changing practice. See our disclaimer and disclosures. Spotted an error? Tell us.